WO2011148962A1 - Novel heterocyclic compound or salt thereof - Google Patents

Novel heterocyclic compound or salt thereof Download PDF

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Publication number
WO2011148962A1
WO2011148962A1 PCT/JP2011/061939 JP2011061939W WO2011148962A1 WO 2011148962 A1 WO2011148962 A1 WO 2011148962A1 JP 2011061939 W JP2011061939 W JP 2011061939W WO 2011148962 A1 WO2011148962 A1 WO 2011148962A1
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group
formula
oxo
naphthyridin
compound
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PCT/JP2011/061939
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French (fr)
Japanese (ja)
Inventor
寿也 野口
文仁 牛山
裕正 堀切
恵子 山本
直哉 小野
哲男 高山
朋子 神山
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大正製薬株式会社
富山化学工業株式会社
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Priority to JP2012517290A priority Critical patent/JP5685589B2/en
Publication of WO2011148962A1 publication Critical patent/WO2011148962A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • the present invention relates to a novel compound having a strong antibacterial activity against gram positive bacteria, gram negative bacteria and resistant bacteria, or a salt thereof, and an antibacterial agent containing them.
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant enterococci
  • PRSP penicillin-resistant pneumococci
  • Non-Patent Document 1 discloses a quinolone compound effective for MRSA.
  • Patent Documents 2-7 disclose a compound having a mechanism of action different from existing drugs.
  • Patent Document 8 discloses a compound having a spiro ring skeleton characteristic of the structure.
  • a bond including a dotted line connecting X 2 and Y 1 represents a single bond or a double bond
  • Z 1 represents a nitrogen atom or formula CR 1
  • Z 2 represents a nitrogen atom or formula CR 2
  • Z 3 represents a nitrogen atom or formula CR 3
  • Z 4 represents a nitrogen atom or formula CR 4 .
  • Z 5 represents a nitrogen atom or formula CR 5
  • Z 6 represents a nitrogen atom or formula CR 6
  • X 1 represents a C 1-4 alkylene group which may be substituted with an oxo group
  • X 2 represents a bond when
  • X 3 represents a C 1-4 alkylene group, a formula NR 10 (CH 2 ) m , a formula SO n , or a bond
  • R 10 is the same or different and represents a hydrogen atom or a C 1-6 alkyl group
  • m and n are the same or different and represent 0, 1, or 2
  • R 7 represents a C 3-6 cycloalkyl group, a C 3-6 cycloalkenyl group, an aryl group, a monocyclic heterocyclic group, or a bicyclic heterocyclic group
  • the C 3-6 cycloalkyl group, C 3-6 cycloalkenyl group, aryl group, monocyclic heterocyclic group, and bicyclic heterocyclic group are a C 1-6 alkoxy group, a hydroxy group, a halogen atom, A C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, a C 2
  • the compound of the formula [I] or a salt thereof has a strong antibacterial activity against gram positive bacteria, gram negative bacteria and resistant bacteria.
  • C xy means that the carbon number is from x to y.
  • C 1-6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert -Butoxy, pentyloxy, isopentyloxy, hexyloxy and the like.
  • the halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. , Pentyl, isopentyl, hexyl and the like.
  • the C 1-6 hydroxyalkyl group means a group in which any one hydrogen atom of the C 1-6 alkyl group is substituted with a hydroxy group.
  • the C 1-6 haloalkyl group means a group in which any hydrogen atom of the C 1-6 alkyl group is substituted with a halogen atom, and examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl and the like. Can do.
  • the number of halogen atom substitutions is preferably 1 to 3.
  • the C 1-6 haloalkoxy group means a group in which any hydrogen atom of the above C 1-6 alkoxy group is substituted with a halogen atom, and examples thereof include fluoromethoxy, difluoromethoxy, trifluoromethoxy and the like. .
  • the number of halogen atom substitutions is preferably 1 to 3.
  • the C 3-6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the C 3-6 cycloalkenyl group is cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.
  • the C 2-7 alkanoyl group means a linear or branched alkanoyl group having 2 to 7 carbon atoms, and examples thereof include acetyl, propionyl, butyryl, isovaleryl, pivaloyl and the like.
  • the C 1-4 alkylene group means a linear or branched alkylene group having 1 to 4 carbon atoms, and examples thereof include methylene, ethylene, propylene, butylene and the like.
  • monocyclic heterocyclic groups include furyl, thienyl, 2-pyrrolyl, imidazolyl, 3-pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, imidazolidinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, piperazinyl, 2-piperidyl , 3-piperidyl, 4-piperidyl, 2-piperazinyl, 2-morpholinyl, 2-thiomorpholinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl and the like.
  • the monocyclic heterocyclic group includes 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms, and is preferably 5- or 6-membered.
  • Bicyclic heterocyclic groups include, for example, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, 1H-indazolyl, purinyl, coumarinyl, chromenyl Quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, quinuclidinyl, 1,3-benzodioxanyl, 1,4-benzodioxanyl, benzomorpholinyl, benzomorpholonyl, 2 , 3-dihydro (1,4) dioxino (2,3-c) pyridin-7-yl, 3,4-d
  • aryl group examples include phenyl, naphthyl, anthracenyl, phenanthrenyl and the like.
  • Examples of the salt of the compound of the formula [I] include a salt of a known basic group such as an amino group or an acidic group such as a phenolic hydroxyl group or a carboxyl group.
  • Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, acetic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; And salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid
  • salts with organic carboxylic acids such as tartaric acid, formic acid, acetic acid, citric acid, trichloroacetic acid and trifluoroacetic acid
  • salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid
  • salts in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Salts with nitrogenous organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine and N, N′-dibenzylethylenediamine Can be mentioned.
  • alkali metals such as sodium and potassium
  • alkaline earth metals such as calcium and magnesium
  • ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Salts with nitrogenous organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohex
  • preferred salts of the compound of the formula [I] include pharmacologically acceptable salts.
  • the compound of the present invention or a salt thereof may form a hydrate or a solvate, and these are also included in the present invention.
  • preferable compounds include the following compounds.
  • a compound in which Z 1 is formula CR 1 is preferred, and a compound in which formula CH is more preferred.
  • a compound in which Z 2 is a nitrogen atom or the formula CH is preferred.
  • Compounds in which Z 3 is a nitrogen atom or the formula CH are preferred.
  • Compounds in which Z 4 is formula CR 4 are preferred, and compounds of formula CH are more preferred.
  • a compound in which Z 5 is formula CR 5 is preferable, and a compound in which R 5 is a C 1-6 alkoxy group or a halogen atom is more preferable.
  • a compound in which Z 6 is formula CR 6 is preferred, and a compound in which formula CH is more preferred.
  • a compound in which X 1 is a C 1-2 alkylene group which may be substituted with an oxo group is preferable, and a C 1-2 alkylene group substituted with an oxo group is more preferable.
  • a compound in which X 2 is a bond (a bond including a dotted line connecting X 2 and Y 1 is a single bond) is preferable.
  • Y 1 is a hydroxy group, a halogen atom, a C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 2-7 alkanoyl group, a phenyl group, a formula —NR 13 R 14 , a formula —CO 2 R 13 , and
  • a compound which is a spiro ring group selected from the following formula group [III], optionally substituted by 1 to 3 groups selected from the group consisting of formula —CONR 13 R 14 is preferably an unsubstituted formula group
  • a compound having a spiro ring group selected from [III] is more preferable,
  • a compound having a spiro ring group selected from the following formula group [IV] is even more preferable.
  • a compound in which X 3 is a C 1-4 alkylene group, a formula NR 10 , a formula SO n , or a bond is preferred, and a compound in which a bond is preferred.
  • R 7 is an aryl group, a monocyclic heterocyclic group, or a bicyclic heterocyclic group, and the aryl group, monocyclic heterocyclic group, and bicyclic heterocyclic group are a C 1-6 alkoxy group, a hydroxy group, Halogen atom, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 haloalkoxy group, C 2-7 alkanoyl group, monocyclic heterocyclic group, formula —NR 11 R 12 , formula —CO 2 R 11 and a compound optionally substituted with 1 to 5 substituents selected from the group consisting of —CONR 11 R 12, preferably 1 to 3 selected from a halogen atom and a C 1-6 alkyl group
  • formulation adjuvants such as excipients, carriers and diluents usually used for formulation may be appropriately mixed.
  • excipients such as excipients, carriers and diluents usually used for formulation
  • these are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, It can be administered orally or parenterally in the form of a patch, ointment or injection.
  • the administration method, the dose and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient.
  • oral administration or parenteral administration for example, injection, infusion, administration to the rectal site, etc.
  • 0.01 to 1000 mg / kg per day can be divided into 1 to several doses. Good.
  • the compound of the formula [I] of the present invention is a gram-positive bacterium, a gram-negative bacterium, an anaerobic bacterium, or a non-drug-containing bacterium such as a multidrug-resistant Staphylococcus aureus, a multidrug-resistant pneumococci, or a vancomycin-resistant enterococci. Excellent antibacterial activity against typical acid-fast bacteria.
  • Z 1 -Z 6 , X 3 , and R 7 are as defined above.
  • X 1a represents a C 1-3 alkylene group
  • Y 1b represents a spiro ring group having a nitrogen atom in the spiro ring and bonded to the adjacent hydrogen atom.
  • the compound of the formula [1a] can be produced by a method described in International Publication No. 06/137485, International Publication No. 07/138974, or the like, or a method analogous thereto.
  • the present compound of the formula [1] can be produced by reacting the compound of the formula [1a] with the compound of the formula [1b] in the presence of a reducing agent.
  • This reaction may be performed by a method described in WO 06/46552 pamphlet or the like or a method according thereto.
  • the amount of the compound of the formula [1b] and the reducing agent used may be 1 to 20 times mol with respect to the compound of the formula [1a].
  • L 1 represents a leaving group, and examples of L 1 include a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • the compound of the formula [2a] can be produced by a method described in International Publication No. 06/137485, International Publication No. 07/138974, or the like, or a method analogous thereto.
  • the compound of the present invention of the formula [2] can be produced by reacting the compound of the formula [2a] with the formula [1b] in the presence or absence of a base.
  • This reaction may be performed by the method described in US Pat. No. 6,603,005 or the like, or a method analogous thereto.
  • the amount of the compound of the formula [1b] and optionally used base may be 1-20 times mol with respect to the compound of the formula [2a].
  • Z 1 -Z 6 , X 1a , X 3 , Y 1b and R 7 are as defined above.
  • the compound of the present invention of the formula [3] can be produced by reacting the compound of the formula [3a] with the compound of the formula [1b] using a condensing agent in the presence or absence of a base.
  • This reaction is carried out according to the method described in WO03 / 010138, WO03 / 087098 and Izumiya et al., Basics and Experiments of Peptide Synthesis, 89-142, 1985, Maruzen et al. What is necessary is just to perform according to the method.
  • the use amount of the base, the compound of formula [1b], and the condensing agent that are optionally used may be 1 to 20 moles compared to the compound of formula [3a].
  • Z 1 -Z 6 , X 1 -X 3 , Y 1 , R 7 , and L 1 are as defined above.
  • the compound of the formula [4a] can be produced by a method described in International Publication No. 06/137485, International Publication No. 07/138974, or the like, or a method analogous thereto.
  • the compound of the present invention of the formula [I] can be produced by reacting the compound of the formula [4a] with the compound of the formula [4b] in the presence or absence of a base.
  • the use amount of the base and the compound of the formula [4b] used as required may be 1 to 20 times the mol of the compound of the formula [4a].
  • Z 1 -Z 6 , X 1 , X 2 , R 7 , and L 1 are as defined above.
  • Y 1a represents a spiro ring group having a nitrogen atom in the spiro ring, and the nitrogen atom is bonded to an adjacent hydrogen atom, and
  • X 3b represents a C 1-4 alkylene group.
  • the compound of the present invention of the formula [5] can be produced by reacting the compound of the formula [5a] with the compound of the formula [5b] in the presence or absence of a base.
  • This reaction may be performed by the method described in US Pat. No. 6,603,005 or the like, or a method analogous thereto.
  • the amount of the compound of the formula [5b] and optionally used base may be 1-20 times mol with respect to the compound of the formula [5a].
  • Z 1 -Z 6 , X 1 , X 2 , R 7 , and Y 1a are as defined above.
  • X 3c represents a C 1-3 alkylene group.
  • the compound of the present invention of the formula [6] can be produced by reacting the compound of the formula [5a] with the compound of the formula [6b] in the presence of a reducing agent.
  • This reaction may be carried out by the method described in WO 06/46552 pamphlet or the like or a method analogous thereto.
  • the amount of the compound of the formula [6b] and the reducing agent used may be 1-20 times mol with respect to the compound of the formula [5a].
  • a base when using a base in the reaction of each production method, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, potassium hydroxide
  • sodium hydroxide, lithium hydroxide, sodium amide, sodium methoxide, tert-butoxypotassium, sodium hydride, lithium hydride, triethylamine, diisopropylethylamine, dimethylaniline, diethylaniline, pyridine, pyrrolidine and N-methylmorpholine can be mentioned.
  • lithium aluminum hydride for example, lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, diisobutylaluminum hydride, etc., boranes, sodium And sodium amalgam and the like.
  • electrolytic reduction using copper or platinum as a cathode catalytic reduction using Raney nickel, platinum oxide or palladium black, reduction using “zinc-acid”, or the like can also be used.
  • the solvent is not particularly limited as long as it is stable under the reaction conditions and is inert and does not interfere with the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and ethylene glycol monomethyl ether Ethers such as; sulfoxides such as dimethyl sulfoxide; esters such as ethyl acetate; N, N-dimethylformamide, N, N-dimethylacetoa
  • amides and water such as de and 1-methyl-2-pyrrolidone, and the like, it may be used which are mixed.
  • reaction can be carried out by selecting an appropriate temperature in the range of ⁇ 78 ° C. to the boiling point of the solvent used for the reaction, under normal pressure or under pressure, under microwave irradiation, or the like.
  • the mixing ratio in the eluent is a volume ratio.
  • each abbreviation has the following meaning.
  • DMSO-d6 heavy dimethyl sulfoxide
  • the obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: ethyl acetate], and ethyl (7-methoxy-2-oxo-2H-quinolin-1-yl) ethyl acetate 322 mg was obtained.
  • the obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: ethyl acetate] and (2-oxo-2H- (1,7) -naphthyridin-1-yl) 112 mg of ethyl acetate was obtained.
  • a colorless oil of 3- (7-methoxy-2) was prepared in the same manner as in Reference Example 7 using 300 mg of 7-methoxy-1H- (1,5) -naphthyridin-2-one and 463 mg of ethyl 3-bromopropionate. There was obtained 207 mg of ethyl -oxo-2H- (1,5) -naphthyridin-1-yl) propionate.
  • N-Butyllithium (2.77 mol / L n-hexane solution) (463 ⁇ L) was added dropwise to a tetrahydrofuran (5.0 mL) solution of diisopropylethylamine (172 ⁇ L) under ice cooling, and the mixture was stirred for 10 minutes. After cooling to ⁇ 78 ° C., 300 mg of ethyl N-tert-butoxycarbonylpiperidine-4-carboxylate was added and stirred for 1 hour.
  • 6-iodo-2,3-dihydrobenzo (1,4) dioxin 341 mg, tert-butyl 1-oxo-2,6-diazaspiro (3.5) nonane-6-carboxylate 300 mg, copper iodide 25 mg, phosphorus 660 mg of potassium acid n-hydrate and 41.1 ⁇ L of (1R, 2R) -N, N′-dimethylcyclohexane-1,2-diamine were suspended in 10 mL of N, N-dimethylformamide and incubated at 110 ° C. for 15.5 hours. Stir. 30 mL of water and 100 mL of ethyl acetate were added to the reaction mixture, and the organic layer was separated.
  • tert-Butyl 9- (2- (7-Fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -3,9-diazaspiro (5.5) undecane-3-carboxylate 1- (2- (3,9-diazaspiro (5.5) undecan-3-yl) ethyl) -7-fluoro-1H- (1,5) was prepared in the same manner as in Reference Example 13 using 438 mg. 318 mg of naphthyridin-2-one hydrochloride was obtained.
  • tert-butyl 7- (2- (7-fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -2,7-diazaspiro (4.4) nonane-2-carboxylate Using 105 mg, in the same manner as in Reference Example 13, colorless solid 1- (2- (2,7-diazaspiro (4.4) non-2-yl) ethyl) -7-fluoro-1H— 92 mg of hydrochloride of (1,5) -naphthyridin-2-one was obtained.
  • a yellow oil was obtained. This was suspended in 50 mL of 2-propanol, 10 mL of 2-propanol solution of 2 mol / L hydrochloric acid was added, and the mixture was stirred at 50 ° C. for 21 hours.
  • tert-Butyl 8- (2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -2,8-diazaspiro (4.5) decane-2-carboxylate 290 mg was dissolved in 5 mL of 1,4-dioxane, 5 mL of 1,4-dioxane solution of 4 mol / L hydrochloric acid was added, and the mixture was stirred at room temperature for 4 hours.
  • tert-butyl 3-oxo-2,8-diazaspiro (4.5) decane-8-carboxylate was dissolved in 2 mL of N, N-dimethylformamide, and 14 mg of 60% sodium hydride was added. Further, a solution of 60 mg of 7-chloromethyl-2,3-dihydro- (1,4) dioxyno (2,3-c) pyridine in 2 mL of N, N-dimethylformamide-2 mL of tetrahydrofuran was added, and the mixture was stirred at 70 ° C. for 15 hours. Stir.
  • reaction mixture was returned to room temperature, 10 mL of water and 10 mL of ethyl acetate were added, and the organic layer was separated.
  • the organic layer was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2- (2,3-dihydro- (1,4) dioxyno (2, 3-c) 108 mg of pyridin-7-ylmethyl) -3-oxo-2,8-diazaspiro (4.5) decane-8-carboxylate was obtained.
  • tert-Butyl 1 ′-(2,3-dihydrobenzo (b) (1,4) dioxin-6-yl) -5′-oxo-8-azaspiro (bicyclo (3.2.1) octane-3, 1 ′-(2,3-dihydrobenzo (b) (1,4) dioxin-6-yl) -8 was prepared in the same manner as in Reference Example 15 using 3 mg of 3′-pyrrolidine) -8-carboxylate. -181 mg of azaspiro (bicyclo (3.2.1) octane-3,3'-pyrrolidin) -5'-one was obtained.
  • Benzyl 4-((2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-ylamino) methyl) -4-hydroxypiperidine-1-carboxylate 51 mg was dissolved in 2 mL of chloroform. , 0.05 mL of triethylamine and 38 mg of bis (trichloromethyl) carbonate were added, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (3 mL) and chloroform (5 mL) were added to the reaction mixture, and the organic layer was separated.
  • Benzyl 3- (2,3-dihydro- (1,4) dioxino (2,3-c) pyridin-7-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decane -8-Carboxylate (63 mg) was dissolved in ethanol (3 mL), 7.5% palladium carbon (22 mg) was added, and the mixture was stirred at 40 ° C. for 6 hours under hydrogen atmosphere. Insoluble matter was filtered off, and the filtrate was evaporated under reduced pressure to give 3- (2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-yl)-as a white solid.
  • tert-Butyl (2- (3-methoxy-6-oxo-6H-pyrido (2,3-b) pyrazin-5-yl) acetate (980 mg) was dissolved in ethyl acetate (5 mL), and 4 mol / L hydrochloric acid in ethyl acetate 10 mL was added, and the mixture was stirred at room temperature for 20 hours, the insoluble material was collected by filtration, washed with 50 mL of ethyl acetate, and dried to give (2- (3-methoxy-6-oxo-6H-pyrido (2 , 3-b) Pyrazin-5-yl) acetic acid hydrochloride 504 mg was obtained.
  • tert-butyl 1-oxa-6-azaspiro (2.5) octane-6-carboxylate 210 mg and 2,3-dihydro- (1,4) dioxyno (2,3-b) pyridin-6-amine 150 mg
  • tert-butyl 4-(((2,3-dihydro- (1,4) dioxyno (2,3-b) pyridin-6-yl) amino in the form of a brown oil was used.
  • 294 mg of methyl) -4-hydroxypiperidine-1-carboxylate were obtained.
  • tert-Butyl 3- (2,3-dihydro- (1,4) dioxino (2,3-b) pyridin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5 )
  • 153 mg of decane-8-carboxylate was dissolved in 2 mL of chloroform, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to make it basic.
  • 2-Bromo-5H-pyrido (3,2-d) pyrimidin-6-one (200 mg) and sodium hydrogen carbonate (297 mg) are suspended in a mixed solvent of 60 mL of ethanol and 60 mL of tetrahydrofuran, and 20 mg of 10% palladium on carbon is added under a hydrogen atmosphere. Stir for hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 220 mg of 5H-pyrido (3,2-d) pyrimidin-6-one (crude purified product) as a light brown solid.
  • tert-butyl 3- (2,3-dihydrobenzo (b) (1,4) dithiin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decane-8-
  • the same operation as in Reference Example 58 was carried out using 33 mg of carboxylate, to give a pale brown solid of 3- (2,3-dihydrobenzo (b) (1,4) dithiin-6-yl) -1-oxa-3 , 8-diazaspiro (4.5) decan-2-one 14 mg was obtained.
  • tert-Butyl 6-Amino-2-azaspiro (3.3) heptane-2-carboxylate 119 mg and 2,3-dihydro- (1,4) dioxyno (2,3-c) pyridine-7-carbaldehyde 89 mg was dissolved in chloroform (5 mL), acetic acid (46 ⁇ L) was added, and the mixture was stirred at room temperature for 3 hr. 250 mg of sodium triacetoxyborohydride was added and stirred at room temperature for 2 hours.
  • tert-butyl 6-(((2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-yl) methyl) amino) -2-azaspiro (3.3) heptane-2 -Using a carboxylate of 130 mg and following the same procedure as in Reference Example 58, a pale yellow oily N-((2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-yl) 88 mg of methyl) -2-azaspiro (3.3) heptane-6-amine were obtained.
  • tert-Butyl 7- (2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -2,7-diazaspiro (4.4) nonane-2-carboxylate Using 105 mg, in the same manner as in Reference Example 13, 1- (2- (2,7-diazaspiro (4.4) non-2-yl) ethyl) -7-methoxy-1H— in the form of a brown solid 125 mg of (1,5) naphthyridin-2-one hydrochloride was obtained.
  • Second Step 140 mg of the residue obtained in the first step and 3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxa-3,8-diazaspiro (4.5) decane- 173 mg of 2-one was suspended in 10 mL of chloroform, 0.42 mL of triethylamine, 204 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 35 mg of 1-hydroxybenzotriazole monohydrate were added, Stir for days. Chloroform 100mL and water 20mL were added to the reaction liquid, and the organic layer was fractionated.
  • Example 5 105 mg ethyl (2-oxo-2H- (1,7) -naphthyridin-1-yl) acetate and 3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxa-3,
  • the same operation as in Example 5 was carried out using 124 mg of 8-diazaspiro (4.5) decan-2-one, and 1- (2- (3- (2,3-dihydrobenzo (1,4 ) Dioxin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-yl) -2-oxoethyl) -1H- (1,7) -naphthyridine-2- On 204 mg was obtained.
  • reaction mixture was ice-cooled, 43 mg of sodium triacetoxyborohydride was added, and the mixture was allowed to warm to room temperature and stirred for 3 hr.
  • the reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: ethyl acetate] to give 1- (2- (2- (2,3-Dihydrobenzo (1,4) dioxin-6-yl) -1-oxo-2,7-diazaspiro (3.5) non-7-yl) ethyl) -7-methoxy-1H 32 mg of (1,5) naphthyridin-2-one was obtained.
  • the reaction mixture was diluted with 100 mL of ethyl acetate, washed successively with 10 mL of water and 10 mL of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Ltd., Chromatorex-NH, eluent: chloroform]. Further, 10 mL of chloroform and 150 mL of hexane were added to the purified product, and the precipitate was collected by filtration and dried to give 3- (3-fluoro-4-methylphenyl) -8- (2- (7-methoxy-2-) as a white solid.
  • Test example 1 Sensitivity measurement test 1 The test substance was dissolved in dimethyl sulfoxide, and antibacterial activity (MIC) was measured by a micro liquid dilution method according to the standard method of CLSI (Clinical and Laboratory Standards Institute).
  • the test strain used was Staphylococcus aureus (MSSA, MRSA).
  • MSSA Staphylococcus aureus
  • the cells cultured overnight at 35 ° C. on a heart infusion agar plate were suspended in Mueller Hinton medium so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution.
  • About 0.005 mL of the inoculated bacterial solution was inoculated into a cation-adjusted Mueller Hinton medium (100 ⁇ L / well) containing a test substance, and cultured overnight at 35 ° C.
  • the lowest test substance concentration at which no bacterial growth was observed macroscopically was defined as MIC ( ⁇ g / mL). The results are shown in Table 1. The part where the numerical value is not described indicates that the test is not performed.
  • Test Example 2 Staphylococcus aureus Mouse Systemic Infection Test
  • a group of 8 animals was used. (4) Judgment of effect The infection treatment effect was based on the survival number 7 days after bacterial inoculation. In the non-treatment group, all cases died by 1 day after the bacterial inoculation, but in Example 4, 7 out of 8 cases were observed 7 days after the bacterial inoculation, indicating in vivo antibacterial activity.
  • Test Example 3 Measurement of inhibitory activity against Staphylococcus aureus-derived topoisomerase IV S. aureus Topoisomerase IV Decatenation Kit (Inspiralis) was used for measurement.
  • 198 ⁇ L of 5 ⁇ Assay Buffer 198 ⁇ L of 5 ⁇ Assay Buffer, 66 ⁇ L of 0.1 ⁇ g / ⁇ L kinetoplast DNA solution and 462 ⁇ L of sterilized ultrapure water were added to prepare a reaction base solution A.
  • 22 ⁇ L of reaction base solution A and 3 ⁇ L of the compound of Example 26 or cyproxacin (CPFX) prepared to a 10-fold concentration were added.
  • topoisomerase IV solution diluted to 0.16 U / ⁇ L using Dilution Buffer was added. The whole volume was incubated at 37 ° C. for 30 minutes. After the reaction, 5 ⁇ L of a reaction stop solution (0.5 M EDTA containing 0.1% BPB) was added, and 20 ⁇ L was electrophoresed on a 1% agarose gel. After electrophoresis, the agarose gel was stained in a 2 ⁇ g / mL ethidium bromide solution, an image was captured, and the amount of each DNA was determined.
  • a reaction stop solution 0.5 M EDTA containing 0.1% BPB
  • the amounts of single-stranded and circular DNA bands in the enzyme-free group and the enzyme-added group not containing the compound of Example 26 or CPFX were 0% and 100%, respectively, and the drug concentration when the reaction product was 50%. It was calculated some IC 50 (IC 50 deca Te National activity). Both the compound of Example 26 and CPFX had an IC 50 of 1 ⁇ g / mL or less.
  • Test Example 4 Measurement of inhibitory activity against S. aureus-derived DNA gyrase S. aureus DNA Gyrase Supercoiling Assay Kit (Inspiralis) was used for measurement.
  • a basic reaction solution B was prepared by adding 210 ⁇ L of 5 ⁇ Assay Buffer, 17.5 ⁇ L of relaxed pBR322 DNA solution and 542.5 ⁇ L of sterilized ultrapure water to an Eppendorf tube.
  • 22 ⁇ L of reaction base solution B and 3 ⁇ L of the compound of Example 26 or CPFX prepared to a 10-fold concentration were added.
  • 5 ⁇ L of DNA gyrase solution diluted to 0.25 U / ⁇ L using Dilution Buffer was added.
  • the whole volume was incubated at 37 ° C. for 30 minutes. After the reaction, 5 ⁇ L of a reaction stop solution was added, and 20 ⁇ L was electrophoresed on a 1% agarose gel. After electrophoresis, the agarose gel was stained in a 2 ⁇ g / mL ethidium bromide solution, an image was taken in, and the amount of each DNA was determined. That is, the drug concentration when the reaction product is 50% when the amount of the supercoiled DNA band in the enzyme-free group and the enzyme-added group not containing the compound of Example 26 or CPFX is 0% and 100%, respectively. It was calculated IC 50 (IC 50 of supercoiling activity). The IC 50 of the compound of Example 26 was 1 ⁇ g / mL or less. On the other hand, IC 50 of CPFX was 12 [mu] g / mL.
  • the heterocyclic compound of the present invention or a salt thereof is useful as an excellent antibacterial agent because it has strong antibacterial activity and high safety.

Abstract

Disclosed is a medicament having a strong antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, and resistant bacteria. A compound represented by formula [I] or a salt thereof is useful as an antibacterial agent. In formula [I], a bond containing a dotted line and connecting X2 to Y1 represents a single bond or a double bond; Z1, Z2, Z3, Z4, Z5, and Z6 each represent a nitrogen atom, formula: CH, or the like; X1 represents a C1-4 alkylene group which may be substituted by an oxo group; X2 represents a bonding hand or formula: CH; Y1 represents a spirocyclic group selected from a group of formulae (II); X3 represents a C1-4 alkylene group, formula: NR10(CH2)m, formula: SOn, or a bonding hand; and R7 represents a C3-6 cycloalkyl group, a C3-6 cycloalkenyl group, an aryl group, a monocyclic heterocyclic group, a bicyclic heterocyclic group, or the like.

Description

新規な複素環化合物又はその塩Novel heterocyclic compound or salt thereof
　本発明は、グラム陽性菌、グラム陰性菌及び耐性菌に対して強い抗菌活性を有する新規な化合物又はその塩及びそれらを含有する抗菌剤に関する。 The present invention relates to a novel compound having a strong antibacterial activity against gram positive bacteria, gram negative bacteria and resistant bacteria, or a salt thereof, and an antibacterial agent containing them.
　医療現場において、感染症の治療のために種々の抗生物質や合成抗菌剤が使用されてきた。しかしながら、近年、メチシリン耐性黄色ブドウ球菌（ＭＲＳＡ）、バンコマイシン耐性腸球菌（ＶＲＥ）及びペニシリン耐性肺炎球菌（ＰＲＳＰ）などの耐性菌が出現している。そのような耐性菌に感染した患者の治療が重要な課題となっている。加えて、複数の薬剤に対して耐性を獲得した多剤耐性菌が出現している。多剤耐性菌による感染症は、難治性の疾病として、世界的に大きな問題となっている。 In the medical field, various antibiotics and synthetic antibacterial agents have been used for the treatment of infectious diseases. However, in recent years, resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant pneumococci (PRSP) have emerged. Treatment of patients infected with such resistant bacteria is an important issue. In addition, multidrug-resistant bacteria that have acquired resistance to multiple drugs have emerged. Infectious diseases caused by multidrug-resistant bacteria are a major problem worldwide as an intractable disease.
　これらの耐性菌に有効な抗生物質の登場が強く望まれており、細菌由来の酵素をターゲットとした薬剤開発が行われている。例えば、細菌がDNA複製に必須な酵素として有するII型トポイソメラーゼであるtopoisomerase IV及びDNA gyraseの反応を阻害することにより、抗菌活性を示すことが見出されており（非特許文献１）、国際公開第９９／０７６８２号パンフレット（特許文献１）には、ＭＲＳＡに有効とするキノロン系化合物が開示されている。また、既存の薬剤とは異なる作用メカニズムを有する化合物も多数開示されている（例えば特許文献２－７）。さらに、構造に特徴的なスピロ環骨格を有する化合物も開示されている（特許文献８）。 The advent of antibiotics effective against these resistant bacteria is strongly desired, and drug development targeting bacteria-derived enzymes is being carried out. For example, it has been found that by inhibiting the reaction of topoisomerase IV, which is a type II topoisomerase that bacteria have as an essential enzyme for DNA replication, and DNA gyrase (Non-Patent Document 1), it has been shown to exhibit antibacterial activity. No. 99/07682 pamphlet (Patent Document 1) discloses a quinolone compound effective for MRSA. In addition, many compounds having a mechanism of action different from existing drugs have been disclosed (for example, Patent Documents 2-7). Furthermore, a compound having a spiro ring skeleton characteristic of the structure is also disclosed (Patent Document 8).
国際公開第９９／０７６８２号パンフレットWO99 / 07682 pamphlet 国際公開第２００４／００２４９０号パンフレットInternational Publication No. 2004/002490 Pamphlet 国際公開第２００４／００２９９２号パンフレットInternational Publication No. 2004/002992 Pamphlet 国際公開第２００６／１３４３７８号パンフレットInternational Publication No. 2006/134378 Pamphlet 国際公開第２００６／１３７４８５号パンフレットInternational Publication No. 2006/137485 Pamphlet 国際公開第２００７／１３８９７４号パンフレットInternational Publication No. 2007/138974 Pamphlet 国際公開第２００８／００９７００号パンフレットInternational Publication No. 2008/009700 pamphlet 国際公開第２００８／０２６１７２号パンフレットInternational Publication No. 2008/026172 Pamphlet
　グラム陽性菌、グラム陰性菌及び耐性菌に対して強い抗菌活性を有し、高い安全性を有する薬剤の開発が望まれている。 Development of drugs with strong antibacterial activity against Gram-positive bacteria, Gram-negative bacteria and resistant bacteria and high safety is desired.
　このような状況下において、本発明者らは、鋭意検討を行った結果、式［Ｉ］ Under such circumstances, the present inventors have conducted intensive studies, and as a result, the formula [I]
Figure JPOXMLDOC01-appb-I000005
Figure JPOXMLDOC01-appb-I000005
（式中、
Ｘ２とＹ１を結ぶ点線を含む結合は、単結合、又は二重結合を示し、
Ｚ１は、窒素原子又は式ＣＲ１を示し、Ｚ２は、窒素原子又は式ＣＲ２を示し、Ｚ３は、窒素原子又は式ＣＲ３を示し、Ｚ４は、窒素原子又は式ＣＲ４を示し、Ｚ５は、窒素原子又は式ＣＲ５を示し、Ｚ６は、窒素原子又は式ＣＲ６を示し、
Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、及びＲ６は、同一又は異なって、水素原子、Ｃ１－６アルコキシ基、ヒドロキシ基、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６ハロアルキル基、Ｃ１－６ハロアルコキシ基、Ｃ３－６シクロアルキル基、シアノ基、ニトロ基、Ｃ２－７アルカノイル基、単環複素環基、式－ＮＲ８Ｒ９、式－ＣＯ２Ｒ８、又は式－ＣＯＮＲ８Ｒ９を示し、
Ｒ８、及びＲ９は、同一又は異なって、水素原子、又はＣ１－６アルキル基を示し、
Ｘ１は、オキソ基で置換されていてもよいＣ１－４アルキレン基を示し、
Ｘ２は、Ｘ２とＹ１を結ぶ点線を含む結合が単結合のとき結合手を示し、Ｘ２とＹ１を結ぶ点線を含む結合が二重結合のとき式ＣＨを示し、
Ｙ１は、ヒドロキシ基、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６ヒドロキシアルキル基、Ｃ２－７アルカノイル基、フェニル基、式－ＮＲ１３Ｒ１４、式－ＣＯ２Ｒ１３、及び式－ＣＯＮＲ１３Ｒ１４からなる群から選ばれる１～３個の基で置換されていてもよい、以下の式群［ＩＩ］から選ばれるスピロ環基を示し、各スピロ環基中の窒素原子がＮ－オキシドであっても良く、
Ｒ１３、及びＲ１４は、同一又は異なって、水素原子、又はＣ１－６アルキル基を示し、 (Where
A bond including a dotted line connecting X 2 and Y 1 represents a single bond or a double bond,
Z 1 represents a nitrogen atom or formula CR 1 , Z 2 represents a nitrogen atom or formula CR 2 , Z 3 represents a nitrogen atom or formula CR 3 , and Z 4 represents a nitrogen atom or formula CR 4 . Z 5 represents a nitrogen atom or formula CR 5 ; Z 6 represents a nitrogen atom or formula CR 6 ;
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are the same or different and each represents a hydrogen atom, a C 1-6 alkoxy group, a hydroxy group, a halogen atom, a C 1-6 alkyl group, C 1 -6 haloalkyl group, C 1-6 haloalkoxy group, C 3-6 cycloalkyl group, cyano group, nitro group, C 2-7 alkanoyl group, monocyclic heterocyclic group, formula -NR 8 R 9 , formula -CO 2 R 8 or the formula -CONR 8 R 9
R 8 and R 9 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group,
X 1 represents a C 1-4 alkylene group which may be substituted with an oxo group,
X 2 represents a bond when a bond including a dotted line connecting X 2 and Y 1 is a single bond, and represents a formula CH when a bond including a dotted line connecting X 2 and Y 1 is a double bond,
Y 1 represents a hydroxy group, a halogen atom, a C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 2-7 alkanoyl group, a phenyl group, a formula —NR 13 R 14 , a formula —CO 2 R 13 , and A spiro ring group selected from the following formula group [II], which may be substituted with 1 to 3 groups selected from the group consisting of the formula —CONR 13 R 14 , and a nitrogen atom in each spiro ring group May be N-oxide,
R 13 and R 14 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group,
Figure JPOXMLDOC01-appb-I000006
Figure JPOXMLDOC01-appb-I000006
Ｘ３は、Ｃ１－４アルキレン基、式ＮＲ１０（ＣＨ２）ｍ、式ＳＯｎ、又は結合手を示し、
Ｒ１０は、同一又は異なって、水素原子、又はＣ１－６アルキル基を示し、ｍ、及びｎは、同一又は異なって、０、１、又は２を示し、
Ｒ７は、Ｃ３－６シクロアルキル基、Ｃ３－６シクロアルケニル基、アリール基、単環複素環基、又は二環複素環基を示し、
ここで、該Ｃ３－６シクロアルキル基、Ｃ３－６シクロアルケニル基、アリール基、単環複素環基、及び二環複素環基は、Ｃ１－６アルコキシ基、ヒドロキシ基、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６ハロアルキル基、Ｃ１－６ハロアルコキシ基、Ｃ２－７アルカノイル基、単環複素環基、式－ＮＲ１１Ｒ１２ 、式－ＣＯ２Ｒ１１、及び式－ＣＯＮＲ１１Ｒ１２からなる群から選ばれる１～５個の置換基で置換されていてもよく、
Ｒ１１、及びＲ１２は、同一又は異なって、水素原子、又はＣ１－６アルキル基を示す。）で表される化合物又はその塩が、強い抗菌活性を有することを見出し、本発明を完成した。 X 3 represents a C 1-4 alkylene group, a formula NR 10 (CH 2 ) m , a formula SO n , or a bond,
R 10 is the same or different and represents a hydrogen atom or a C 1-6 alkyl group; m and n are the same or different and represent 0, 1, or 2;
R 7 represents a C 3-6 cycloalkyl group, a C 3-6 cycloalkenyl group, an aryl group, a monocyclic heterocyclic group, or a bicyclic heterocyclic group,
Here, the C 3-6 cycloalkyl group, C 3-6 cycloalkenyl group, aryl group, monocyclic heterocyclic group, and bicyclic heterocyclic group are a C 1-6 alkoxy group, a hydroxy group, a halogen atom, A C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, a C 2-7 alkanoyl group, a monocyclic heterocyclic group, a formula —NR 11 R 12 , a formula —CO 2 R 11 , and May be substituted with 1 to 5 substituents selected from the group consisting of the formula -CONR 11 R 12 ,
R 11 and R 12 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group. ) Or a salt thereof was found to have strong antibacterial activity, and the present invention was completed.
　式［Ｉ］の化合物又はその塩は、グラム陽性菌、グラム陰性菌及び耐性菌に対して強い抗菌活性を有する。 The compound of the formula [I] or a salt thereof has a strong antibacterial activity against gram positive bacteria, gram negative bacteria and resistant bacteria.
　本発明において、Ｃｘ－ｙとは炭素数がｘからｙであることを意味する。 In the present invention, C xy means that the carbon number is from x to y.
　Ｃ１－６アルコキシ基とは、炭素数が１から６の直鎖状又は分枝鎖状のアルコキシ基を意味し、例えばメトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ペンチルオキシ、イソペンチルオキシ、ヘキシルオキシなどを挙げることができる。 C 1-6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert -Butoxy, pentyloxy, isopentyloxy, hexyloxy and the like.
　ハロゲン原子とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子である。 The halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
　Ｃ１－６アルキル基とは、炭素数が１から６の直鎖状又は分岐鎖状のアルキル基を意味し、例えばメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチル、ヘキシルなどを挙げることができる。 C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. , Pentyl, isopentyl, hexyl and the like.
　Ｃ１－６ヒドロキシアルキル基とは、上記Ｃ１－６アルキル基の任意の１つの水素原子がヒドロキシ基で置換された基を意味し、例えばヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル、ヒドロキシブチル、ヒドロキシペンチル、ヒドロキシヘキシルなどを挙げることができる。 The C 1-6 hydroxyalkyl group means a group in which any one hydrogen atom of the C 1-6 alkyl group is substituted with a hydroxy group. For example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxy Examples include pentyl and hydroxyhexyl.
　Ｃ１－６ハロアルキル基とは、上記Ｃ１－６アルキル基の任意の水素原子がハロゲン原子で置換された基を意味し、例えばフルオロメチル、ジフルオロメチル、トリフルオロメチル、トリクロロメチルなどを挙げることができる。ハロゲン原子の置換数は１～３が好ましい。 The C 1-6 haloalkyl group means a group in which any hydrogen atom of the C 1-6 alkyl group is substituted with a halogen atom, and examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl and the like. Can do. The number of halogen atom substitutions is preferably 1 to 3.
　Ｃ１－６ハロアルコキシ基とは、上記Ｃ１－６アルコキシ基の任意の水素原子がハロゲン原子で置換された基を意味し、例えばフルオロメトキシ、ジフルオロメトキシ、トリフルオロメトキシなどを挙げることができる。ハロゲン原子の置換数は１～３が好ましい。 The C 1-6 haloalkoxy group means a group in which any hydrogen atom of the above C 1-6 alkoxy group is substituted with a halogen atom, and examples thereof include fluoromethoxy, difluoromethoxy, trifluoromethoxy and the like. . The number of halogen atom substitutions is preferably 1 to 3.
　Ｃ３－６シクロアルキル基とは、シクロプロピル、シクロブチル、シクロペンチル、又はシクロヘキシルである。 The C 3-6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
　Ｃ３－６シクロアルケニル基とは、シクロプロペニル、シクロブテニル、シクロペンテニル、又はシクロヘキセニルである。 The C 3-6 cycloalkenyl group is cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.
　Ｃ２－７アルカノイル基とは、炭素数が２から７の直鎖状又は分枝鎖状のアルカノイル基を意味し、例えばアセチル、プロピオニル、ブチリル、イソバレリル、ピバロイルなどを挙げることができる。 The C 2-7 alkanoyl group means a linear or branched alkanoyl group having 2 to 7 carbon atoms, and examples thereof include acetyl, propionyl, butyryl, isovaleryl, pivaloyl and the like.
　Ｃ１－４アルキレン基とは、炭素数が１から４の直鎖状又は分岐鎖状のアルキレン基を意味し、例えばメチレン、エチレン、プロピレン、ブチレンなどを挙げることができる。 The C 1-4 alkylene group means a linear or branched alkylene group having 1 to 4 carbon atoms, and examples thereof include methylene, ethylene, propylene, butylene and the like.
　単環複素環基とは、例えばフリル、チエニル、２－ピロリル、イミダゾリル、３－ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、チアジアゾリル、イミダゾリジニル、ピリジル、ピリミジニル、ピリダジニル、ピラジル、ピロリジニル、ピペラジニル、２－ピペリジル、３－ピペリジル、４－ピペリジル、２－ピペラジニル、２－モルホリニル、２－チオモルホリニル、ピラニル、テトラヒドロピラニル、テトラヒドロチオピラニルなどを挙げることができる。単環複素環基は、環構成原子として、窒素原子、酸素原子、及び硫黄原子から選ばれた１から３個のヘテロ原子を含み、５又は６員であることが好ましい。 Examples of monocyclic heterocyclic groups include furyl, thienyl, 2-pyrrolyl, imidazolyl, 3-pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, imidazolidinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, piperazinyl, 2-piperidyl , 3-piperidyl, 4-piperidyl, 2-piperazinyl, 2-morpholinyl, 2-thiomorpholinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl and the like. The monocyclic heterocyclic group includes 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms, and is preferably 5- or 6-membered.
　二環複素環基とは、例えばベンゾフラニル、イソベンゾフラニル、ベンゾチエニル、インドリル、イソインドリル、インドリジニル、ベンズイミダゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、１Ｈ－インダゾリル、プリニル、クマリニル、クロメニル、キノリル、イソキノリル、フタラジニル、ナフチリジニル、キノキサリニル、キナゾリニル、シンノリニル、クロマニル、イソクロマニル、キヌクリジニル、１，３－ベンゾジオキサニル、１，４－ベンゾジオキサニル、ベンゾモルホリニル、ベンゾモルホロニル、２，３－ジヒドロ（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル、３，４－ジヒドロ－２Ｈ－ピリド（４，３－ｂ）（１，４）オキサジン－７－イル、３－オキソ－３，４－ジヒドロ－２Ｈ－ピリド（３，２－ｂ）（１，４）オキサジン－６－イル、３－オキソ－３，４－ジヒドロ－２Ｈ－ピリド（３，２－ｂ）（１，４）チアジン－６－イル、３－オキソ－３，４－ジヒドロ－２Ｈ－ベンゾチアジン－６－イル、３，４－ジヒドロ－２Ｈ－ピラノ（２，３－ｃ）ピリジン－６－イル、３，４－ジヒドロ－２Ｈ－（１，４）ジオキセピノ（２，３－ｃ）ピリジン－８－イル、（１，３）ジオキソロ（４，５－ｃ）ピリジン－６－イル、６－オキシド－２，３－ジヒドロ（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル、７－オキソ－５，６，７，８－テトラヒドロ－１，８－ナフチリジン－２－イル、５，６，７，８－テトラヒドロキノキサリン－２－イル、１，４－ベンゾジチアニル、チエノ（３，２－ｂ）チオフェン－２－イル、７－オキソ－７，８－ジヒドロ－６Ｈ－ピリミド（５，４－ｂ）（１，４）オキサジン－４－イルなどを挙げることができる。 Bicyclic heterocyclic groups include, for example, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, 1H-indazolyl, purinyl, coumarinyl, chromenyl Quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, quinuclidinyl, 1,3-benzodioxanyl, 1,4-benzodioxanyl, benzomorpholinyl, benzomorpholonyl, 2 , 3-dihydro (1,4) dioxino (2,3-c) pyridin-7-yl, 3,4-dihydro-2H-pyrido (4,3-b) (1,4) oxazin-7-yl, 3-oxo-3,4-dihi Ro-2H-pyrido (3,2-b) (1,4) oxazin-6-yl, 3-oxo-3,4-dihydro-2H-pyrido (3,2-b) (1,4) thiazine 6-yl, 3-oxo-3,4-dihydro-2H-benzothiazin-6-yl, 3,4-dihydro-2H-pyrano (2,3-c) pyridin-6-yl, 3,4-dihydro- 2H- (1,4) dioxepino (2,3-c) pyridin-8-yl, (1,3) dioxolo (4,5-c) pyridin-6-yl, 6-oxide-2,3-dihydro ( 1,4) dioxyno (2,3-c) pyridin-7-yl, 7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl, 5,6,7,8- Tetrahydroquinoxalin-2-yl, 1,4-benzodithianyl, thieno (3,2-b) Thiophene-2-yl, 7-oxo-7,8-dihydro -6H- pyrimido (-5,4 b) (1,4) such oxazin-4-yl and the like.
　アリール基とは、例えばフェニル、ナフチル、アントラセニル、フェナントレニルなどを挙げることができる。 Examples of the aryl group include phenyl, naphthyl, anthracenyl, phenanthrenyl and the like.
　式［Ｉ］の化合物の塩としては、通常、知られているアミノ基などの塩基性基又はフェノール性ヒドロキシル基若しくはカルボキシル基などの酸性基における塩を挙げることができる。 Examples of the salt of the compound of the formula [I] include a salt of a known basic group such as an amino group or an acidic group such as a phenolic hydroxyl group or a carboxyl group.
　塩基性基における塩としては、例えば、塩酸、臭化水素酸及び硫酸などの鉱酸との塩；酒石酸、ギ酸、酢酸、クエン酸、トリクロロ酢酸及びトリフルオロ酢酸などの有機カルボン酸との塩；並びにメタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、メシチレンスルホン酸及びナフタレンスルホン酸などのスルホン酸との塩などが挙げられる。 Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, acetic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; And salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
　酸性基における塩としては、例えば、ナトリウム及びカリウムなどのアルカリ金属との塩；カルシウム及びマグネシウムなどのアルカリ土類金属との塩；アンモニウム塩；並びにトリメチルアミン、トリエチルアミン、トリブチルアミン、ピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン、ジエチルアミン、ジシクロヘキシルアミン、プロカイン、ジベンジルアミン、Ｎ－ベンジル－β－フェネチルアミン及びＮ，Ｎ’－ジベンジルエチレンジアミンなどの含窒素有機塩基との塩などを挙げることができる。 Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Salts with nitrogenous organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine and N, N′-dibenzylethylenediamine Can be mentioned.
　さらに、上記、塩の中で式［Ｉ］の化合物の好ましい塩としては、薬理学的に許容される塩が挙げられる。 Furthermore, among the above salts, preferred salts of the compound of the formula [I] include pharmacologically acceptable salts.
　また、本発明化合物又はその塩は、水和物又は溶媒和物を形成することがあり、それらも本発明に包含される。 In addition, the compound of the present invention or a salt thereof may form a hydrate or a solvate, and these are also included in the present invention.
　本発明の式［Ｉ］の化合物において、好ましい化合物としては、以下の化合物が挙げられる。 In the compound of the formula [I] of the present invention, preferable compounds include the following compounds.
　Ｚ１が式ＣＲ１である化合物が好ましく、式ＣＨである化合物がより好ましい。
　Ｚ２が窒素原子又は式ＣＨである化合物が好ましい。
　Ｚ３が窒素原子又は式ＣＨである化合物が好ましい。
　Ｚ４が式ＣＲ４である化合物が好ましく、式ＣＨである化合物がより好ましい。
　Ｚ５が式ＣＲ５である化合物が好ましく、Ｒ５がＣ１－６アルコキシ基、又はハロゲン原子である化合物がより好ましい。
　Ｚ６が式ＣＲ６である化合物が好ましく、式ＣＨである化合物がより好ましい。
　Ｘ１がオキソ基で置換されていてもよいＣ１－２アルキレン基である化合物が好ましく、オキソ基で置換されたＣ１－２アルキレン基であることがより好ましい。
　Ｘ２が結合手である（Ｘ２とＹ１を結ぶ点線を含む結合は単結合）化合物が好ましい。
　Ｙ１が、ヒドロキシ基、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６ヒドロキシアルキル基、Ｃ２－７アルカノイル基、フェニル基、式－ＮＲ１３Ｒ１４、式－ＣＯ２Ｒ１３、及び式－ＣＯＮＲ１３Ｒ１４からなる群から選ばれる１～３個の基で置換されていてもよい、以下の式群［ＩＩＩ］から選ばれるスピロ環基である化合物が好ましく、無置換の式群［ＩＩＩ］から選ばれるスピロ環基である化合物がより好ましく、 A compound in which Z 1 is formula CR 1 is preferred, and a compound in which formula CH is more preferred.
A compound in which Z 2 is a nitrogen atom or the formula CH is preferred.
Compounds in which Z 3 is a nitrogen atom or the formula CH are preferred.
Compounds in which Z 4 is formula CR 4 are preferred, and compounds of formula CH are more preferred.
A compound in which Z 5 is formula CR 5 is preferable, and a compound in which R 5 is a C 1-6 alkoxy group or a halogen atom is more preferable.
A compound in which Z 6 is formula CR 6 is preferred, and a compound in which formula CH is more preferred.
A compound in which X 1 is a C 1-2 alkylene group which may be substituted with an oxo group is preferable, and a C 1-2 alkylene group substituted with an oxo group is more preferable.
A compound in which X 2 is a bond (a bond including a dotted line connecting X 2 and Y 1 is a single bond) is preferable.
Y 1 is a hydroxy group, a halogen atom, a C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 2-7 alkanoyl group, a phenyl group, a formula —NR 13 R 14 , a formula —CO 2 R 13 , and A compound which is a spiro ring group selected from the following formula group [III], optionally substituted by 1 to 3 groups selected from the group consisting of formula —CONR 13 R 14 , is preferably an unsubstituted formula group A compound having a spiro ring group selected from [III] is more preferable,
Figure JPOXMLDOC01-appb-I000007
以下の式群［ＩＶ］から選ばれるスピロ環基である化合物がよりさらに好ましい。
Figure JPOXMLDOC01-appb-I000007
A compound having a spiro ring group selected from the following formula group [IV] is even more preferable.
Figure JPOXMLDOC01-appb-I000008
Figure JPOXMLDOC01-appb-I000008
　Ｘ３がＣ１－４アルキレン基、式ＮＲ１０、式ＳＯｎ、又は結合手である化合物が好ましく、結合手である化合物がより好ましい。
　Ｒ７がアリール基、単環複素環基、又は二環複素環基であって、該アリール基、単環複素環基、及び二環複素環基が、Ｃ１－６アルコキシ基、ヒドロキシ基、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６ハロアルキル基、Ｃ１－６ハロアルコキシ基、Ｃ２－７アルカノイル基、単環複素環基、式－ＮＲ１１Ｒ１２ 、式－ＣＯ２Ｒ１１、及び式－ＣＯＮＲ１１Ｒ１２からなる群から選ばれる１～５個の置換基で置換されていてもよい化合物が好ましく、ハロゲン原子、及びＣ１－６アルキル基から選ばれる１～３個の置換基で置換されてもよいアリール基、又は二環複素環基である化合物が好ましい。 A compound in which X 3 is a C 1-4 alkylene group, a formula NR 10 , a formula SO n , or a bond is preferred, and a compound in which a bond is preferred.
R 7 is an aryl group, a monocyclic heterocyclic group, or a bicyclic heterocyclic group, and the aryl group, monocyclic heterocyclic group, and bicyclic heterocyclic group are a C 1-6 alkoxy group, a hydroxy group, Halogen atom, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 haloalkoxy group, C 2-7 alkanoyl group, monocyclic heterocyclic group, formula —NR 11 R 12 , formula —CO 2 R 11 and a compound optionally substituted with 1 to 5 substituents selected from the group consisting of —CONR 11 R 12, preferably 1 to 3 selected from a halogen atom and a C 1-6 alkyl group The compound which is the aryl group which may be substituted by the substituent of, or a bicyclic heterocyclic group is preferable.
　本発明の式［Ｉ］の化合物を医薬として用いる場合、通常、製剤化に使用される賦形剤、担体及び希釈剤などの製剤補助剤を適宜混合してもよい。これらは、常法にしたがって、錠剤、カプセル剤、散剤、シロップ剤、顆粒剤、丸剤、懸濁剤、乳剤、液剤、粉体製剤、坐剤、点眼剤、点鼻剤、点耳剤、貼付剤、軟膏剤又は注射剤などの形態で、経口又は非経口で投与することができる。また投与方法、投与量及び投与回数は、患者の年齢、体重及び症状に応じて適宜選択することができる。通常、成人に対しては、経口又は非経口（例えば、注射、点滴及び直腸部位への投与など）投与により、１日、0.01～1000mg／kgを１回から数回に分割して投与すればよい。 When the compound of the formula [I] of the present invention is used as a medicine, formulation adjuvants such as excipients, carriers and diluents usually used for formulation may be appropriately mixed. These are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, It can be administered orally or parenterally in the form of a patch, ointment or injection. Further, the administration method, the dose and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. Usually, for adults, oral administration or parenteral administration (for example, injection, infusion, administration to the rectal site, etc.), 0.01 to 1000 mg / kg per day can be divided into 1 to several doses. Good.
　本発明の式［Ｉ］の化合物は、多剤耐性の黄色ブドウ球菌、多剤耐性の肺炎球菌、バンコマイシン耐性の腸球菌などの耐性菌を含むグラム陽性菌、グラム陰性菌、嫌気性菌又は非定型抗酸菌などに対し、優れた抗菌力を示す。 The compound of the formula [I] of the present invention is a gram-positive bacterium, a gram-negative bacterium, an anaerobic bacterium, or a non-drug-containing bacterium such as a multidrug-resistant Staphylococcus aureus, a multidrug-resistant pneumococci, or a vancomycin-resistant enterococci. Excellent antibacterial activity against typical acid-fast bacteria.
　次に、本発明化合物の製造法について説明する。本発明の式［Ｉ］の化合物は、以下に示す方法によって製造することができるが、本発明の化合物の製造方法はこれらに限定されるものではない。 Next, a method for producing the compound of the present invention will be described. Although the compound of the formula [I] of this invention can be manufactured by the method shown below, the manufacturing method of the compound of this invention is not limited to these.
［製造法１］
Figure JPOXMLDOC01-appb-I000009
[Production Method 1]
Figure JPOXMLDOC01-appb-I000009
　式中、Ｚ１－Ｚ６、Ｘ３、及びＲ７は、前記と同義である。Ｘ１ａは、Ｃ１－３アルキレン基を示し、Ｙ１ｂは、スピロ環内に窒素原子を有し、該窒素原子が隣接する水素原子に結合するスピロ環基を示す。式［１ａ］の化合物は、国際公開第０６／１３７４８５号パンフレット、及び国際公開第０７／１３８９７４号パンフレット等に記載された方法又はそれに準じた方法で製造することができる。 In the formula, Z 1 -Z 6 , X 3 , and R 7 are as defined above. X 1a represents a C 1-3 alkylene group, and Y 1b represents a spiro ring group having a nitrogen atom in the spiro ring and bonded to the adjacent hydrogen atom. The compound of the formula [1a] can be produced by a method described in International Publication No. 06/137485, International Publication No. 07/138974, or the like, or a method analogous thereto.
　式［１］の本発明化合物は、還元剤の存在下、式［１ａ］の化合物と式［１ｂ］の化合物を反応させることで製造することができる。この反応は、国際公開第０６／４６５５２号パンフレット等に記載された方法又はそれに準じた方法で行えばよい。この反応において、式［１ｂ］の化合物及び還元剤の使用量は、式［１ａ］の化合物に対して１－２０倍モルであればよい。 The present compound of the formula [1] can be produced by reacting the compound of the formula [1a] with the compound of the formula [1b] in the presence of a reducing agent. This reaction may be performed by a method described in WO 06/46552 pamphlet or the like or a method according thereto. In this reaction, the amount of the compound of the formula [1b] and the reducing agent used may be 1 to 20 times mol with respect to the compound of the formula [1a].
［製造法２］
Figure JPOXMLDOC01-appb-I000010
[Production Method 2]
Figure JPOXMLDOC01-appb-I000010
　式中、Ｚ１－Ｚ６、Ｘ１、Ｘ３、Ｙ１ｂ、及びＲ７は、前記と同義である。Ｌ１は、脱離基を示し、Ｌ１の例として、塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ基、ｐ－トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等が挙げられる。式［２ａ］の化合物は、国際公開第０６／１３７４８５号パンフレット、及び国際公開第０７／１３８９７４号パンフレット等に記載された方法又はそれに準じた方法で製造することができる。 In the formula, Z 1 -Z 6 , X 1 , X 3 , Y 1b , and R 7 are as defined above. L 1 represents a leaving group, and examples of L 1 include a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. The compound of the formula [2a] can be produced by a method described in International Publication No. 06/137485, International Publication No. 07/138974, or the like, or a method analogous thereto.
　式［２］の本発明化合物は、塩基の存在下又は非存在下、式［２ａ］の化合物と式［１ｂ］を反応させることで製造することができる。この反応は、米国特許第６６０３００５号明細書等に記載された方法又はそれに準じた方法で行えばよい。この反応において、式［１ｂ］の化合物及び所望により使用される塩基の使用量は、式［２ａ］の化合物に対して１－２０倍モルであればよい。 The compound of the present invention of the formula [2] can be produced by reacting the compound of the formula [2a] with the formula [1b] in the presence or absence of a base. This reaction may be performed by the method described in US Pat. No. 6,603,005 or the like, or a method analogous thereto. In this reaction, the amount of the compound of the formula [1b] and optionally used base may be 1-20 times mol with respect to the compound of the formula [2a].
［製造法３］
Figure JPOXMLDOC01-appb-I000011
[Production Method 3]
Figure JPOXMLDOC01-appb-I000011
　式中、Ｚ１－Ｚ６、Ｘ１ａ、Ｘ３、Ｙ１ｂ、及びＲ７は、前記と同義である。 In the formula, Z 1 -Z 6 , X 1a , X 3 , Y 1b and R 7 are as defined above.
　式［３］の本発明化合物は、塩基の存在下又は非存在下、縮合剤を用いて式［３ａ］の化合物と式［１ｂ］の化合物を反応させることで製造することができる。この反応は、国際公開第０３／０１０１３８号パンフレット、国際公開第０３／０８７０９８号パンフレット及び泉屋ら、ペプチド合成の基礎と実験、第８９－１４２頁、１９８５年、丸善等に記載された方法又はそれに準じた方法で行えばよい。この反応において、所望により使用される塩基、式［１ｂ］の化合物、及び縮合剤の使用量は、式［３ａ］の化合物に対して１－２０倍モルであればよい。 The compound of the present invention of the formula [3] can be produced by reacting the compound of the formula [3a] with the compound of the formula [1b] using a condensing agent in the presence or absence of a base. This reaction is carried out according to the method described in WO03 / 010138, WO03 / 087098 and Izumiya et al., Basics and Experiments of Peptide Synthesis, 89-142, 1985, Maruzen et al. What is necessary is just to perform according to the method. In this reaction, the use amount of the base, the compound of formula [1b], and the condensing agent that are optionally used may be 1 to 20 moles compared to the compound of formula [3a].
［製造法４］
Figure JPOXMLDOC01-appb-I000012
[Production Method 4]
Figure JPOXMLDOC01-appb-I000012
　式中、Ｚ１－Ｚ６、Ｘ１－Ｘ３、Ｙ１、Ｒ７、及びＬ１は、前記と同義である。式［４ａ］の化合物は、国際公開第０６／１３７４８５号パンフレット、及び国際公開第０７／１３８９７４号パンフレット等に記載された方法又はそれに準じた方法で製造することができる。 In the formula, Z 1 -Z 6 , X 1 -X 3 , Y 1 , R 7 , and L 1 are as defined above. The compound of the formula [4a] can be produced by a method described in International Publication No. 06/137485, International Publication No. 07/138974, or the like, or a method analogous thereto.
　式［Ｉ］の本発明化合物は、塩基の存在下又は非存在下、式［４ａ］の化合物と式［４ｂ］の化合物を反応させることで製造することができる。この反応において、所望により使用される塩基及び式［４ｂ］の化合物の使用量は、式［４ａ］の化合物に対して１－２０倍モルであればよい。 The compound of the present invention of the formula [I] can be produced by reacting the compound of the formula [4a] with the compound of the formula [4b] in the presence or absence of a base. In this reaction, the use amount of the base and the compound of the formula [4b] used as required may be 1 to 20 times the mol of the compound of the formula [4a].
［製造法５］
Figure JPOXMLDOC01-appb-I000013
[Production Method 5]
Figure JPOXMLDOC01-appb-I000013
　式中、Ｚ１－Ｚ６、Ｘ１、Ｘ２、Ｒ７、及びＬ１は、前記と同義である。Ｙ１ａは、スピロ環内に窒素原子を有し、該窒素原子が隣接する水素原子に結合するスピロ環基を示し、Ｘ３ｂは、Ｃ１－４アルキレン基を示す。 In the formula, Z 1 -Z 6 , X 1 , X 2 , R 7 , and L 1 are as defined above. Y 1a represents a spiro ring group having a nitrogen atom in the spiro ring, and the nitrogen atom is bonded to an adjacent hydrogen atom, and X 3b represents a C 1-4 alkylene group.
　式［５］の本発明化合物は、塩基の存在下又は非存在下、式［５ａ］の化合物と式［５ｂ］の化合物を反応させることで製造することができる。この反応は、米国特許第６６０３００５号明細書等に記載された方法又はそれに準じた方法で行えばよい。この反応において、式［５ｂ］の化合物及び所望により使用される塩基の使用量は、式［５ａ］の化合物に対して１－２０倍モルであればよい。 The compound of the present invention of the formula [5] can be produced by reacting the compound of the formula [5a] with the compound of the formula [5b] in the presence or absence of a base. This reaction may be performed by the method described in US Pat. No. 6,603,005 or the like, or a method analogous thereto. In this reaction, the amount of the compound of the formula [5b] and optionally used base may be 1-20 times mol with respect to the compound of the formula [5a].
［製造法６］
Figure JPOXMLDOC01-appb-I000014
[Production Method 6]
Figure JPOXMLDOC01-appb-I000014
　式中、Ｚ１－Ｚ６、Ｘ１、Ｘ２、Ｒ７、及びＹ１ａは、前記と同義である。Ｘ３ｃは、Ｃ１－３アルキレン基を示す。 In the formula, Z 1 -Z 6 , X 1 , X 2 , R 7 , and Y 1a are as defined above. X 3c represents a C 1-3 alkylene group.
　式［６］の本発明化合物は、還元剤の存在下、式［５ａ］の化合物と式［６ｂ］の化合物を反応させることで製造することができる。この反応は、国際公開第０６／４６５５２号パンフレットなどに記載された方法又はそれに準じた方法で行えばよい。この反応において、式［６ｂ］の化合物及び還元剤の使用量は、式［５ａ］の化合物に対して１－２０倍モルであればよい。 The compound of the present invention of the formula [6] can be produced by reacting the compound of the formula [5a] with the compound of the formula [6b] in the presence of a reducing agent. This reaction may be carried out by the method described in WO 06/46552 pamphlet or the like or a method analogous thereto. In this reaction, the amount of the compound of the formula [6b] and the reducing agent used may be 1-20 times mol with respect to the compound of the formula [5a].
　特段の記載がない場合、各製造法の反応で塩基を用いる場合の塩基としては、例えば、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸水素ナトリウム、炭酸水素カリウム、酢酸ナトリウム、酢酸カリウム、水酸化カリウム、水酸化ナトリウム、水酸化リチウム、ナトリウムアミド、ナトリウムメトキシド、ｔｅｒｔ－ブトキシカリウム、水素化ナトリウム、水素化リチウム、トリエチルアミン、ジイソプロピルエチルアミン、ジメチルアニリン、ジエチルアニリン、ピリジン、ピロリジン及びＮ－メチルモルホリンなどが挙げられる。 Unless otherwise specified, as a base when using a base in the reaction of each production method, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, potassium hydroxide Sodium hydroxide, lithium hydroxide, sodium amide, sodium methoxide, tert-butoxypotassium, sodium hydride, lithium hydride, triethylamine, diisopropylethylamine, dimethylaniline, diethylaniline, pyridine, pyrrolidine and N-methylmorpholine Can be mentioned.
　縮合剤としては、例えば、Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロホスファート、１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩、ジシクロヘキシルカルボジイミド、カルボニルジイミダゾール、２－クロロ－１－メチルピリジニウムヨウ化物塩、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリン塩化物塩、Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロホスファート及びヘキサフルオロリン酸＝（ベンゾトリアゾール－１－イルオキシ）トリピロリジノホスホニウム等が挙げられる。 Examples of the condensing agent include O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, 1- (3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyldiimidazole, 2-chloro-1-methylpyridinium iodide salt, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4- Methylmorpholine chloride salt, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate and hexafluorophosphoric acid = (benzotriazole-1- Yloxy) tripyrrolidinophosphonium and the like.
　還元剤としては、例えば、水素化アルミニウムリチウム、水素化トリアセトキシホウ素ナトリウム、水素化シアノホウ素ナトリウム、水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化ジイソブチルアルミニウム等の水素化錯化合物、ボラン類、ナトリウム並びにナトリウムアマルガム等が挙げられる。また、銅又は白金を陰極に用いた電解還元；ラネーニッケル、酸化白金又はパラジウム黒を用いる接触還元並びに「亜鉛－酸」を用いる還元などを用いることもできる。 As the reducing agent, for example, lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, diisobutylaluminum hydride, etc., boranes, sodium And sodium amalgam and the like. Further, electrolytic reduction using copper or platinum as a cathode; catalytic reduction using Raney nickel, platinum oxide or palladium black, reduction using “zinc-acid”, or the like can also be used.
　溶媒としては、当該反応条件下において安定であり、かつ不活性で反応を妨げないものであれば特に制限はなく、例えば、メタノール、エタノール、２－プロパノール及び２－メチル－２－プロパノールなどのアルコール類；塩化メチレン、クロロホルム及びジクロロエタンなどのハロゲン化炭化水素類；ベンゼン、トルエン及びキシレンなどの芳香族炭化水素類；ジオキサン、テトラヒドロフラン、アニソール、エチレングリコールジメチルエーテル、ジエチレングリコールジメチルエーテル、ジエチレングリコールジエチルエーテル及びエチレングリコールモノメチルエーテルなどのエーテル類；ジメチルスルホキシドなどのスルホキシド類；酢酸エチルなどのエステル類；Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド及び１－メチル－２－ピロリドンなどのアミド類並びに水などが挙げられ、これらは混合して使用してもよい。 The solvent is not particularly limited as long as it is stable under the reaction conditions and is inert and does not interfere with the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and ethylene glycol monomethyl ether Ethers such as; sulfoxides such as dimethyl sulfoxide; esters such as ethyl acetate; N, N-dimethylformamide, N, N-dimethylacetoa Such as amides and water, such as de and 1-methyl-2-pyrrolidone, and the like, it may be used which are mixed.
　また反応は、－７８℃から反応に用いる溶媒の沸点の範囲で適切な温度を選択し、常圧下又は加圧下、マイクロウェーブ照射下等で実施することができる。 In addition, the reaction can be carried out by selecting an appropriate temperature in the range of −78 ° C. to the boiling point of the solvent used for the reaction, under normal pressure or under pressure, under microwave irradiation, or the like.
　製造法１－６において、イミノ、アミノ、ヒドロキシ及びカルボキシ基が存在する場合、それらを適宜保護してもよく、それらの保護基を適宜組み替えて反応を行うことができる。 In Production Method 1-6, when imino, amino, hydroxy and carboxy groups are present, they may be appropriately protected, and the reaction can be carried out by appropriately combining these protecting groups.
　製造法１－６において、カルボニル基を有する化合物を反応に用いる場合、カルボニル基を有する化合物の代わりにカルボニル基が保護された化合物を使用することができる。 In production method 1-6, when a compound having a carbonyl group is used in the reaction, a compound having a carbonyl group protected can be used instead of the compound having a carbonyl group.
　つぎに、本発明を参考例及び実施例を挙げて説明するが、本発明はこれらに限定されるものではない。
なお、溶離液における混合比は、容量比である。各参考例、実施例において各略号は、以下の意味を有する。ＤＭＳＯ－ｄ６：重ジメチルスルホキシド Next, the present invention will be described with reference to reference examples and examples, but the present invention is not limited thereto.
The mixing ratio in the eluent is a volume ratio. In each reference example and example, each abbreviation has the following meaning. DMSO-d6: heavy dimethyl sulfoxide
参考例１
Figure JPOXMLDOC01-appb-I000015
Reference example 1
Figure JPOXMLDOC01-appb-I000015
（７－フルオロ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）アセトアルデヒド500mgをメタノール5mLに溶解し、水素化ホウ素ナトリウム164mgを加え、室温にて６時間撹拌した。反応混合物を減圧下で溶媒留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア株式会社、Chromatorex-NH、溶離液；クロロホルム：メタノール＝９：１］で精製し、無色固体状の７－フルオロ－１－（２－ヒドロキシエチル）－１Ｈ－（１，５）ナフチリジン－２－オン282mgを得た。
1H NMR (CHLOROFORM-d)δ 4.06 (2 H, t, J=5.3 Hz), 4.43 (2 H, t, J=5.3 Hz), 6.90 (1 H, d, J=9.2Hz), 7.60 (1 H, dd, J=9.9, 2.1 Hz), 7.94 (1 H, d, J=9.2 Hz), 8.44 (1 H, d, J=2.1 Hz) 500 mg of (7-fluoro-2-oxo-2H- (1,5) -naphthyridin-1-yl) acetaldehyde was dissolved in 5 mL of methanol, 164 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Ltd., Chromatorex-NH, eluent: chloroform: methanol = 9: 1] to give a colorless solid 282 mg of 7-fluoro-1- (2-hydroxyethyl) -1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 4.06 (2 H, t, J = 5.3 Hz), 4.43 (2 H, t, J = 5.3 Hz), 6.90 (1 H, d, J = 9.2 Hz), 7.60 (1 H, dd, J = 9.9, 2.1 Hz), 7.94 (1 H, d, J = 9.2 Hz), 8.44 (1 H, d, J = 2.1 Hz)
参考例２
Figure JPOXMLDOC01-appb-I000016
Reference example 2
Figure JPOXMLDOC01-appb-I000016
７－フルオロ－１－（２－ヒドロキシエチル）－１Ｈ－（１，５）ナフチリジン－２－オン100mgをテトラヒドロフラン10mLに溶解し、氷冷下塩化チオニル0.1mLを加えた。氷冷下１．５時間撹拌した後、反応混合物を減圧下で溶媒留去して、黄色固体状の１－（２－クロロエチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン100mgを得た。
1H NMR (DMSO-d6)δ 3.85 - 3.94 (2 H, m), 4.59 (2 H, t, J=6.6 Hz), 6.86 (1 H, d, J=10.1 Hz), 7.95 - 8.02 (1 H, m), 8.17 - 8.26 (1 H, m), 8.55 - 8.61 (1 H, m) 100 mg of 7-fluoro-1- (2-hydroxyethyl) -1H- (1,5) naphthyridin-2-one was dissolved in 10 mL of tetrahydrofuran, and 0.1 mL of thionyl chloride was added under ice cooling. After stirring for 1.5 hours under ice cooling, the reaction mixture was evaporated under reduced pressure to give 1- (2-chloroethyl) -7-fluoro-1H- (1,5) naphthyridine-2- as a yellow solid. On 100 mg was obtained.
1H NMR (DMSO-d6) δ 3.85-3.94 (2 H, m), 4.59 (2 H, t, J = 6.6 Hz), 6.86 (1 H, d, J = 10.1 Hz), 7.95-8.02 (1 H , m), 8.17-8.26 (1 H, m), 8.55-8.61 (1 H, m)
参考例３
Figure JPOXMLDOC01-appb-I000017
Reference example 3
Figure JPOXMLDOC01-appb-I000017
７－フルオロ－１Ｈ－（１，５）－ナフチリジン－２－オン528mgをＮ，Ｎ－ジメチルホルムアミド5mLに懸濁し、６０％水素化ナトリウム210mgを加え、８０℃にて４０分撹拌した。ブロモ酢酸ｔｅｒｔ－ブチル0.56mLを加え、８０℃にて１時間撹拌した。反応混合物に水20mLとクロロホルム100mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０Ｎ、溶離液；酢酸エチル：ヘキサン＝１：１］で精製し、（７－フルオロ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）酢酸ｔｅｒｔ－ブチル640mgを得た。
1H NMR (CHLOROFORM-d)δ ppm 1.48 (9 H, s), 4.91 (2 H, s), 6.90 (1 H, d, J=9.7 Hz), 7.12 (1 H, dd, J=9.9, 2.2 Hz), 7.93 (1 H, d, J=9.7 Hz), 8.43 (1 H, d, J=2.2 Hz) 528 mg of 7-fluoro-1H- (1,5) -naphthyridin-2-one was suspended in 5 mL of N, N-dimethylformamide, 210 mg of 60% sodium hydride was added, and the mixture was stirred at 80 ° C. for 40 minutes. 0.56 mL of tert-butyl bromoacetate was added and stirred at 80 ° C. for 1 hour. 20 mL of water and 100 mL of chloroform were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60N, eluent; ethyl acetate: hexane = 1: 1], and (7-fluoro-2-oxo-2H- (1 , 5) -Naphthyridin-1-yl) tert-butyl acetate 640 mg was obtained.
1 H NMR (CHLOROFORM-d) δ ppm 1.48 (9 H, s), 4.91 (2 H, s), 6.90 (1 H, d, J = 9.7 Hz), 7.12 (1 H, dd, J = 9.9, 2.2 Hz), 7.93 (1 H, d, J = 9.7 Hz), 8.43 (1 H, d, J = 2.2 Hz)
参考例４
Figure JPOXMLDOC01-appb-I000018
Reference example 4
Figure JPOXMLDOC01-appb-I000018
（７－フルオロ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）酢酸ｔｅｒｔ－ブチル624mgを１，４－ジオキサン5mLに溶解し、4 mol/L塩酸の１，４－ジオキサン溶液10mLを加え、室温にて３０分、さらに６０℃で一晩撹拌した。室温まで冷却後、析出物を濾取し、減圧乾燥して、（７－フルオロ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）酢酸の塩酸塩を865mg得た。
1H NMR (METHANOL-d4)δ 5.09 (2 H, s), 6.91 (1 H, d, J=10.1 Hz), 7.82 (1 H, dd, J=10.5, 1.4 Hz), 8.03 (1 H, d, J=10.1 Hz), 8.51 (1 H, dd, J=2.3, 1.4 Hz) (7-Fluoro-2-oxo-2H- (1,5) -naphthyridin-1-yl) tert-butyl acetate (624 mg) is dissolved in 1,4-dioxane (5 mL), and 4 mol / L hydrochloric acid in 1,4-dioxane is dissolved. 10 mL of the solution was added, and the mixture was stirred at room temperature for 30 minutes and further at 60 ° C. overnight. After cooling to room temperature, the precipitate was collected by filtration and dried under reduced pressure to obtain 865 mg of (7-fluoro-2-oxo-2H- (1,5) -naphthyridin-1-yl) acetic acid hydrochloride.
1H NMR (METHANOL-d4) δ 5.09 (2 H, s), 6.91 (1 H, d, J = 10.1 Hz), 7.82 (1 H, dd, J = 10.5, 1.4 Hz), 8.03 (1 H, d , J = 10.1 Hz), 8.51 (1 H, dd, J = 2.3, 1.4 Hz)
参考例５
Figure JPOXMLDOC01-appb-I000019
Reference Example 5
Figure JPOXMLDOC01-appb-I000019
７－メトキシ－１Ｈ－（１，５）－ナフチリジン－２－オン5.00gを用いて参考例３と同様の操作により、黄色固体状の（７－メトキシ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）酢酸ｔｅｒｔ－ブチル2.26gを得た。
1H NMR (CHLOROFORM-d)δ 1.46 (9 H, s) , 3.94 (3 H, s), 4.95 (2 H, s), 6.78 (1 H, d, J=9.6 Hz), 6.80 (1 H, d, J=2.3 Hz), 7.89 (1 H, d, J=9.6 Hz), 8.29 (1 H, d, J=2.8 Hz) By using the same procedure as in Reference Example 3 using 5.00 g of 7-methoxy-1H- (1,5) -naphthyridin-2-one, (7-methoxy-2-oxo-2H- (1,5 ) -Naphthyridin-1-yl) tert-butyl acetate 2.26 g.
1H NMR (CHLOROFORM-d) δ 1.46 (9 H, s), 3.94 (3 H, s), 4.95 (2 H, s), 6.78 (1 H, d, J = 9.6 Hz), 6.80 (1 H, d, J = 2.3 Hz), 7.89 (1 H, d, J = 9.6 Hz), 8.29 (1 H, d, J = 2.8 Hz)
参考例６
Figure JPOXMLDOC01-appb-I000020
Reference Example 6
Figure JPOXMLDOC01-appb-I000020
（７－メトキシ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）酢酸ｔｅｒｔ－ブチル1.35gを用いて参考例４と同様の操作により、淡黄色固体状の（７－メトキシ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）酢酸の塩酸塩1.28gを得た。
1H NMR (METHANOL-d4)δ 4.06 (3 H, s), 5.17 (2 H, s), 6.92 (1 H, d, J=9.6 Hz), 7.66 (1 H, d, J=2.3 Hz), 8.00 - 8.04 (1 H, m), 8.46 (1 H, d, J=2.3 Hz) (7-Methoxy-2-oxo-2H- (1,5) -naphthyridin-1-yl) tert-butyl acetate (1.35 g) was used in the same manner as in Reference Example 4 to produce (7-methoxy There was obtained 1.28 g of hydrochloride of -2-oxo-2H- (1,5) -naphthyridin-1-yl) acetic acid.
1H NMR (METHANOL-d4) δ 4.06 (3 H, s), 5.17 (2 H, s), 6.92 (1 H, d, J = 9.6 Hz), 7.66 (1 H, d, J = 2.3 Hz), 8.00-8.04 (1 H, m), 8.46 (1 H, d, J = 2.3 Hz)
参考例７
Figure JPOXMLDOC01-appb-I000021
Reference Example 7
Figure JPOXMLDOC01-appb-I000021
７－メトキシ－１Ｈ－キノリン－２－オン 290mgをＮ，Ｎ－ジメチルホルムアミド5mLに懸濁し、６０％水素化ナトリウム213mgを加え、室温にて３０分撹拌した。ブロモ酢酸エチル0.38mLを加え、９０℃にて１７時間撹拌した。反応混合物に水20mLと酢酸エチル100mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル］で精製し、（７－メトキシ－２－オキソ－２Ｈ－キノリン－１－イル）酢酸エチル322mgを得た。
1H NMR (CHLOROFORM-d)δ 1.26 (3 H, t, J=7.1 Hz), 3.87 (3 H, s), 4.24 (2 H, q, J=7.1 Hz), 5.06 (2 H, s), 6.55 (1 H, d, J=1.8 Hz), 6.57 (1 H, d, J=9.2 Hz), 6.82 (1 H, dd, J=8.7, 1.8 Hz), 7.49 (1 H, d, J=8.7 Hz), 7.65 (1 H, d, J=9.2 Hz) 290 mg of 7-methoxy-1H-quinolin-2-one was suspended in 5 mL of N, N-dimethylformamide, 213 mg of 60% sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes. 0.38 mL of ethyl bromoacetate was added, and the mixture was stirred at 90 ° C. for 17 hours. 20 mL of water and 100 mL of ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: ethyl acetate], and ethyl (7-methoxy-2-oxo-2H-quinolin-1-yl) ethyl acetate 322 mg was obtained.
1H NMR (CHLOROFORM-d) δ 1.26 (3 H, t, J = 7.1 Hz), 3.87 (3 H, s), 4.24 (2 H, q, J = 7.1 Hz), 5.06 (2 H, s), 6.55 (1 H, d, J = 1.8 Hz), 6.57 (1 H, d, J = 9.2 Hz), 6.82 (1 H, dd, J = 8.7, 1.8 Hz), 7.49 (1 H, d, J = 8.7 Hz), 7.65 (1 H, d, J = 9.2 Hz)
参考例８
Figure JPOXMLDOC01-appb-I000022
Reference Example 8
Figure JPOXMLDOC01-appb-I000022
１Ｈ－（１，７）－ナフチリジン－２－オン 262mgをＮ，Ｎ－ジメチルホルムアミド5mLに懸濁し、６０％水素化ナトリウム213mgを加え、室温にて３０分撹拌した。ブロモ酢酸エチル0.40mLを加え、９０℃にて１７時間撹拌した。反応混合物に水20mLと酢酸エチル100mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル］で精製し、（２－オキソ－２Ｈ－（１，７）－ナフチリジン－１－イル）酢酸エチル112mgを得た。
1H NMR (CHLOROFORM-d)δ 1.30 (3 H, t, J=7.1 Hz), 4.27 (2 H, q, J=7.1 Hz), 5.13 (2 H, s), 6.93 (1 H, d, J=9.2 Hz), 7.45 (1 H, d, J=5.0 Hz), 7.71 (1 H, d, J=9.2 Hz), 8.48 (1 H, d, J=5.0 Hz), 8.59 (1 H, s) 262 mg of 1H- (1,7) -naphthyridin-2-one was suspended in 5 mL of N, N-dimethylformamide, 213 mg of 60% sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes. 0.40 mL of ethyl bromoacetate was added, and the mixture was stirred at 90 ° C. for 17 hours. 20 mL of water and 100 mL of ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: ethyl acetate] and (2-oxo-2H- (1,7) -naphthyridin-1-yl) 112 mg of ethyl acetate was obtained.
1H NMR (CHLOROFORM-d) δ 1.30 (3 H, t, J = 7.1 Hz), 4.27 (2 H, q, J = 7.1 Hz), 5.13 (2 H, s), 6.93 (1 H, d, J = 9.2 Hz), 7.45 (1 H, d, J = 5.0 Hz), 7.71 (1 H, d, J = 9.2 Hz), 8.48 (1 H, d, J = 5.0 Hz), 8.59 (1 H, s )
参考例９
Figure JPOXMLDOC01-appb-I000023
Reference Example 9
Figure JPOXMLDOC01-appb-I000023
７－メトキシ－１Ｈ－（１，５）－ナフチリジン－２－オン300mg及び３－ブロモプロピオン酸エチル463mgを用いて、参考例７と同様の操作により、無色油状の３－（７－メトキシ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）プロピオン酸エチル207mgを得た。
1H NMR (CHLOROFORM-d)δ 1.18 - 1.29 (3 H, m), 2.77 (2 H, t, J=7.5 Hz), 3.99 (3 H, s), 4.15 (2 H, q, J=7.3 Hz), 4.53 (2 H, t, J=7.5 Hz), 6.75 (1 H, d, J=9.7 Hz), 7.29 (1 H, d, J=2.2 Hz), 7.86 (1 H, d, J=9.7 Hz), 8.26 - 8.31 (1 H, m) A colorless oil of 3- (7-methoxy-2) was prepared in the same manner as in Reference Example 7 using 300 mg of 7-methoxy-1H- (1,5) -naphthyridin-2-one and 463 mg of ethyl 3-bromopropionate. There was obtained 207 mg of ethyl -oxo-2H- (1,5) -naphthyridin-1-yl) propionate.
1H NMR (CHLOROFORM-d) δ 1.18-1.29 (3 H, m), 2.77 (2 H, t, J = 7.5 Hz), 3.99 (3 H, s), 4.15 (2 H, q, J = 7.3 Hz ), 4.53 (2 H, t, J = 7.5 Hz), 6.75 (1 H, d, J = 9.7 Hz), 7.29 (1 H, d, J = 2.2 Hz), 7.86 (1 H, d, J = 9.7 Hz), 8.26-8.31 (1 H, m)
参考例１０
Figure JPOXMLDOC01-appb-I000024
Reference Example 10
Figure JPOXMLDOC01-appb-I000024
７－メトキシ－１Ｈ－キノキサリン－２－オン850mg及びブロモ酢酸エチル1.06mLを用いて、参考例７と同様の操作により、黄色固体状の（７－メトキシ－２－オキソ－２Ｈ－キノキサリン－１－イル）酢酸エチル288mgを得た。
1H NMR (CHLOROFORM-d)δ 1.28 (3 H, t, J=7.1 Hz), 3.90 (3 H, s), 4.25 (2 H, q, J=7.1 Hz), 4.98 (2 H, s), 6.52 (1 H, d, J=2.3 Hz), 6.92 - 6.95 (1 H, m), 7.82 (1 H, d, J=8.7 Hz), 8.18 (1 H, s) By using the same procedure as in Reference Example 7 using 850 mg of 7-methoxy-1H-quinoxalin-2-one and 1.06 mL of ethyl bromoacetate, (7-methoxy-2-oxo-2H-quinoxaline-1- Yl) 288 mg of ethyl acetate was obtained.
1H NMR (CHLOROFORM-d) δ 1.28 (3 H, t, J = 7.1 Hz), 3.90 (3 H, s), 4.25 (2 H, q, J = 7.1 Hz), 4.98 (2 H, s), 6.52 (1 H, d, J = 2.3 Hz), 6.92-6.95 (1 H, m), 7.82 (1 H, d, J = 8.7 Hz), 8.18 (1 H, s)
参考例１１
Figure JPOXMLDOC01-appb-I000025
Reference Example 11
Figure JPOXMLDOC01-appb-I000025
２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イルアミン1.00gをＮ，Ｎ－ジメチルホルムアミド10mLに溶解し、水素化ホウ素ナトリウム346mg及びブロモアセトニトリル1.32mLを加え、室温にて３時間撹拌した。反応混合物に水30mL、酢酸エチル200mL及びトルエン40mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液20mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル：ヘキサン＝１：１］で精製し、（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イルアミノ）アセトニトリル789mgを得た。
1H NMR (CHLOROFORM-d)δ 3.67 (1 H, br. s.), 4.03 (2 H, s), 4.18 - 4.22 (2 H, m), 4.23 - 4.27 (2 H, m), 6.25 (1 H, dd, J=8.7, 2.8 Hz), 6.28 (1 H, d, J=2.8 Hz), 6.78 (1 H, d, J=8.7 Hz) 1.00 g of 2,3-dihydrobenzo (1,4) dioxin-6-ylamine was dissolved in 10 mL of N, N-dimethylformamide, 346 mg of sodium borohydride and 1.32 mL of bromoacetonitrile were added, and the mixture was stirred at room temperature for 3 hours. . 30 mL of water, 200 mL of ethyl acetate and 40 mL of toluene were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with 20 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent; ethyl acetate: hexane = 1: 1] to obtain (2,3-dihydrobenzo (1,4) dioxin. 789 mg of -6-ylamino) acetonitrile was obtained.
1H NMR (CHLOROFORM-d) δ 3.67 (1 H, br.s.), 4.03 (2 H, s), 4.18-4.22 (2 H, m), 4.23-4.27 (2 H, m), 6.25 (1 H, dd, J = 8.7, 2.8 Hz), 6.28 (1 H, d, J = 2.8 Hz), 6.78 (1 H, d, J = 8.7 Hz)
参考例１２
Figure JPOXMLDOC01-appb-I000026
Reference Example 12
Figure JPOXMLDOC01-appb-I000026
ジイソプロピルエチルアミン172μLのテトラヒドロフラン5.0mL溶液に氷冷下、ｎ－ブチルリチウム（2.77mol/L ｎ－ヘキサン溶液）463μLを滴下し、１０分撹拌した。－７８℃まで冷却し、Ｎ－ｔｅｒｔ－ブトキシカルボニルピペリジン－４－カルボン酸エチル300mgを加え、１時間撹拌した。（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イルアミノ）アセトニトリル222mgのテトラヒドロフラン5mL溶液を加え、室温に戻して１８時間撹拌した。反応混合物に水10mL及び酢酸エチル50mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル：ヘキサン＝２：３］で精製して、黄色油状のｔｅｒｔ－ブチル＝２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，７－ジアザスピロ（３．５）ノナン－７－カルボキシラート65mgを得た。
1H NMR (CHLOROFORM-d)δ 1.47 (9 H, s), 1.74 - 1.83 (2 H, m), 1.96 - 2.03 (2 H, m), 3.37 - 3.44 (4 H, m), 3.73 - 3.80 (2 H, m), 4.21 - 4.26 (4 H, m), 6.80 - 6.83 (1 H, m), 6.85 - 6.89 (2 H, m) N-Butyllithium (2.77 mol / L n-hexane solution) (463 μL) was added dropwise to a tetrahydrofuran (5.0 mL) solution of diisopropylethylamine (172 μL) under ice cooling, and the mixture was stirred for 10 minutes. After cooling to −78 ° C., 300 mg of ethyl N-tert-butoxycarbonylpiperidine-4-carboxylate was added and stirred for 1 hour. A solution of 222 mg of (2,3-dihydrobenzo (1,4) dioxin-6-ylamino) acetonitrile in 5 mL of tetrahydrofuran was added, and the mixture was warmed to room temperature and stirred for 18 hours. 10 mL of water and 50 mL of ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent; ethyl acetate: hexane = 2: 3] to give yellow oily tert-butyl = 2- (2, 65 mg of 3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxo-2,7-diazaspiro (3.5) nonane-7-carboxylate was obtained.
1H NMR (CHLOROFORM-d) δ 1.47 (9 H, s), 1.74-1.83 (2 H, m), 1.96-2.03 (2 H, m), 3.37-3.44 (4 H, m), 3.73-3.80 ( 2 H, m), 4.21-4.26 (4 H, m), 6.80-6.83 (1 H, m), 6.85-6.89 (2 H, m)
参考例１３
Figure JPOXMLDOC01-appb-I000027
Reference Example 13
Figure JPOXMLDOC01-appb-I000027
ｔｅｒｔ－ブチル＝２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，７－ジアザスピロ（３．５）ノナン－７－カルボキシラート65mgをクロロホルム1.0mLに溶解し、2 mol/L塩酸の２－プロパノール溶液3.0mLを加え、室温にて１５時間撹拌した。反応混合物を減圧下で溶媒留去して、淡黄色固体状の２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２，７－ジアザスピロ（３．５）ノナン－１－オンの塩酸塩45mgを得た。
1H NMR (DEUTERIUM OXIDE)δ 2.13 - 2.27 (4 H, m), 3.28 (2 H, br. s.), 3.44 - 3.52 (2 H, m), 3.71 - 3.75 (2 H, m), 4.28 - 4.36 (4 H, m), 6.90 - 6.94 (1 H, m), 6.95 - 7.00 (2 H, m) tert-Butyl-2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxo-2,7-diazaspiro (3.5) nonane-7-carboxylate (65 mg) in chloroform (1.0 mL) Then, 3.0 mL of a 2-propanol solution of 2 mol / L hydrochloric acid was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated under reduced pressure to give pale yellow solid 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -2,7-diazaspiro (3.5) nonane- 45 mg of 1-one hydrochloride was obtained.
1H NMR (DEUTERIUM OXIDE) δ 2.13-2.27 (4 H, m), 3.28 (2 H, br.s.), 3.44-3.52 (2 H, m), 3.71-3.75 (2 H, m), 4.28- 4.36 (4 H, m), 6.90-6.94 (1 H, m), 6.95-7.00 (2 H, m)
参考例１４
Figure JPOXMLDOC01-appb-I000028
Reference Example 14
Figure JPOXMLDOC01-appb-I000028
６－ヨード－２，３－ジヒドロベンゾ（１，４）ジオキシン341mg、ｔｅｒｔ－ブチル＝１－オキソ－２，６－ジアザスピロ（３．５）ノナン－６－カルボキシラート300mg、ヨウ化銅25mg、リン酸カリウム・ｎ水和物660mg及び（１Ｒ，２Ｒ）－Ｎ，Ｎ’－ジメチルシクロヘキサン－１，２－ジアミン41.1μLをＮ，Ｎ－ジメチルホルムアミド10mLに懸濁し、１１０℃にて１５．５時間撹拌した。反応混合物に水30mL及び酢酸エチル100mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル：ヘキサン＝１：１］で精製して、無色泡状のｔｅｒｔ－ブチル＝２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，６－ジアザスピロ（３．５）ノナン－６－カルボキシラート442mgを得た。
1H NMR (CHLOROFORM-d)δ 1.42 - 1.56 (10 H, m), 1.74 - 1.83 (1 H, m), 1.89 - 2.01 (2 H, m), 2.86 (1 H, br. s.), 3.23 (1 H, br. s.), 3.33 (1 H, d, J=5.0 Hz), 3.51 (1 H, br. s.), 3.84 - 4.19 (2 H, m), 4.21 - 4.27 (4 H, m), 6.80 - 6.90 (3 H, m) 6-iodo-2,3-dihydrobenzo (1,4) dioxin 341 mg, tert-butyl = 1-oxo-2,6-diazaspiro (3.5) nonane-6-carboxylate 300 mg, copper iodide 25 mg, phosphorus 660 mg of potassium acid n-hydrate and 41.1 μL of (1R, 2R) -N, N′-dimethylcyclohexane-1,2-diamine were suspended in 10 mL of N, N-dimethylformamide and incubated at 110 ° C. for 15.5 hours. Stir. 30 mL of water and 100 mL of ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent; ethyl acetate: hexane = 1: 1] to give colorless foamy tert-butyl = 2- (2 , 3-Dihydrobenzo (1,4) dioxin-6-yl) -1-oxo-2,6-diazaspiro (3.5) nonane-6-carboxylate 442 mg was obtained.
1H NMR (CHLOROFORM-d) δ 1.42-1.56 (10 H, m), 1.74-1.83 (1 H, m), 1.89-2.01 (2 H, m), 2.86 (1 H, br.s.), 3.23 (1 H, br. S.), 3.33 (1 H, d, J = 5.0 Hz), 3.51 (1 H, br. S.), 3.84-4.19 (2 H, m), 4.21-4.27 (4 H , m), 6.80-6.90 (3 H, m)
参考例１５
Figure JPOXMLDOC01-appb-I000029
Reference Example 15
Figure JPOXMLDOC01-appb-I000029
ｔｅｒｔ－ブチル＝２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，６－ジアザスピロ（３．５）ノナン－６－カルボキシラート440mgをクロロホルム3mLに溶解し、2 mol/L塩酸の２－プロパノール溶液5mLを加え、室温にて１４．５時間撹拌した。反応混合物を減圧下溶媒留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア株式会社、Chromatorex-NH、溶離液；酢酸エチル：ヘキサン＝４：１］で精製して、淡黄色油状の２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２，６－ジアザスピロ（３．５）ノナン－１－オン240mgを得た。
1H NMR (CHLOROFORM-d)δ 1.52 - 1.60 (1 H, m), 1.79 - 1.90 (2 H, m), 1.98 - 2.05 (1 H, m), 2.77 - 2.83 (1 H, m), 2.84 - 2.90 (1 H, m), 3.04 (1 H, d, J=12.4 Hz), 3.14 (1 H, d, J=12.8 Hz), 3.37 (1 H, d, J=5.5 Hz), 3.45 (1 H, d, J=5.5 Hz), 4.21 - 4.27 (4 H, m), 6.79 - 6.84 (1 H, m), 6.84 - 6.90 (2 H, m) tert-Butyl-2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxo-2,6-diazaspiro (3.5) nonane-6-carboxylate (440 mg) in 3 mL of chloroform After dissolution, 5 mL of 2-propanol solution of 2 mol / L hydrochloric acid was added and stirred at room temperature for 14.5 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Ltd., Chromatorex-NH, eluent: ethyl acetate: hexane = 4: 1] A yellow oily 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -2,6-diazaspiro (3.5) nonan-1-one (240 mg) was obtained.
1H NMR (CHLOROFORM-d) δ 1.52-1.60 (1 H, m), 1.79-1.90 (2 H, m), 1.98-2.05 (1 H, m), 2.77-2.83 (1 H, m), 2.84- 2.90 (1 H, m), 3.04 (1 H, d, J = 12.4 Hz), 3.14 (1 H, d, J = 12.8 Hz), 3.37 (1 H, d, J = 5.5 Hz), 3.45 (1 H, d, J = 5.5 Hz), 4.21-4.27 (4 H, m), 6.79-6.84 (1 H, m), 6.84-6.90 (2 H, m)
参考例１６
Figure JPOXMLDOC01-appb-I000030
Reference Example 16
Figure JPOXMLDOC01-appb-I000030
６－ヨード－２，３－ジヒドロベンゾ（１，４）ジオキシン157mg及びｔｅｒｔ－ブチル＝３－オキソ－２，８－ジアザスピロ（４．５）デカン－８－カルボキシラート152mgを用いて、参考例１４と同様の操作により、ｔｅｒｔ－ブチル＝２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－８－カルボキシラート279mgを得た。
1H NMR (CHLOROFORM-d)δ 1.46 (9 H, s), 1.62 - 1.68 (4 H, m), 2.50 (2 H, s), 3.27 - 3.35 (2 H, m), 3.54 - 3.62 (4 H, m), 4.22 - 4.28 (4 H, m), 6.85 (1 H, d, J=8.7 Hz), 7.02 (1 H, dd, J=8.7, 2.5 Hz), 7.12 (1 H, d, J=2.5 Hz) Reference Example 14 using 157 mg of 6-iodo-2,3-dihydrobenzo (1,4) dioxin and 152 mg of tert-butyl = 3-oxo-2,8-diazaspiro (4.5) decane-8-carboxylate In the same manner as above, tert-butyl = 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -3-oxo-2,8-diazaspiro (4.5) decane-8-carboxy 279 mg of Lat was obtained.
1H NMR (CHLOROFORM-d) δ 1.46 (9 H, s), 1.62-1.68 (4 H, m), 2.50 (2 H, s), 3.27-3.35 (2 H, m), 3.54-3.62 (4 H , m), 4.22-4.28 (4 H, m), 6.85 (1 H, d, J = 8.7 Hz), 7.02 (1 H, dd, J = 8.7, 2.5 Hz), 7.12 (1 H, d, J = 2.5 Hz)
参考例１７
Figure JPOXMLDOC01-appb-I000031
Reference Example 17
Figure JPOXMLDOC01-appb-I000031
ｔｅｒｔ－ブチル＝２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－８－カルボキシラート248mgを１，４－ジオキサン5mLに溶解し、4 mol/L塩酸の１，４－ジオキサン溶液5mLを加え、５０℃で一晩撹拌した。反応混合物を減圧下溶媒留去し、得られた残留物に飽和炭酸水素ナトリウム水溶液5mL及びクロロホルム20mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去して、２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－３－オン142mgを得た。
1H NMR (CHLOROFORM-d)δ 1.66 (4 H, t, J=5.5 Hz), 2.49 (2 H, s), 2.81 - 2.92 (4 H, m), 3.58 (2 H, s), 4.22 - 4.27 (4 H, m), 6.84 (1 H, d, J=8.7 Hz), 7.04 (1 H, dd, J=8.7, 2.3 Hz), 7.13 (1 H, d, J=2.3 Hz) tert-Butyl-2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -3-oxo-2,8-diazaspiro (4.5) decane-8-carboxylate 248 mg -Dissolved in 5 mL of dioxane, added 5 mL of 1,4-dioxane solution of 4 mol / L hydrochloric acid, and stirred at 50 ° C overnight. The solvent was distilled off from the reaction mixture under reduced pressure, 5 mL of saturated aqueous sodium hydrogen carbonate solution and 20 mL of chloroform were added to the resulting residue, and the organic layer was separated. The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl)- 142 mg of 3-oxo-2,8-diazaspiro (4.5) decan-3-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.66 (4 H, t, J = 5.5 Hz), 2.49 (2 H, s), 2.81-2.92 (4 H, m), 3.58 (2 H, s), 4.22-4.27 (4 H, m), 6.84 (1 H, d, J = 8.7 Hz), 7.04 (1 H, dd, J = 8.7, 2.3 Hz), 7.13 (1 H, d, J = 2.3 Hz)
参考例１８
Figure JPOXMLDOC01-appb-I000032
Reference Example 18
Figure JPOXMLDOC01-appb-I000032
６－ヨード－２，３－ジヒドロベンゾ（１，４）ジオキシン293mg及びｔｅｒｔ－ブチル＝１－オキソ－２，９－ジアザスピロ（５．５）ウンデカン－９－カルボキシラート300mgを用いて、参考例１４と同様の操作により、黄色固体状のｔｅｒｔ－ブチル＝２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，９－ジアザスピロ（５．５）ウンデカン－９－カルボキシラート143mgを得た。
1H NMR (CHLOROFORM-d)δ 1.43 - 1.54 (2 H, m), 1.46 (9 H, s), 1.88 (2 H, d, J=4.6 Hz), 1.95 (2 H, br. s.), 2.13 (2 H, ddd, J=13.6, 9.3, 4.1 Hz), 3.29 (2 H, ddd, J=13.3, 9.2, 3.7 Hz), 3.57 (2 H, t, J=6.0 Hz), 3.75 - 3.81 (2 H, m), 4.24 (4 H, s), 6.66 (1 H, dd, J=8.7, 2.3 Hz), 6.71 (1 H, d, J=2.8 Hz), 6.85 (1 H, d, J=8.3 Hz) Reference Example 14 using 293 mg of 6-iodo-2,3-dihydrobenzo (1,4) dioxine and 300 mg of tert-butyl = 1-oxo-2,9-diazaspiro (5.5) undecane-9-carboxylate In the same manner as above, yellow solid tert-butyl = 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxo-2,9-diazaspiro (5.5) undecane 143 mg of -9-carboxylate was obtained.
1H NMR (CHLOROFORM-d) δ 1.43-1.54 (2 H, m), 1.46 (9 H, s), 1.88 (2 H, d, J = 4.6 Hz), 1.95 (2 H, br.s.), 2.13 (2 H, ddd, J = 13.6, 9.3, 4.1 Hz), 3.29 (2 H, ddd, J = 13.3, 9.2, 3.7 Hz), 3.57 (2 H, t, J = 6.0 Hz), 3.75-3.81 (2 H, m), 4.24 (4 H, s), 6.66 (1 H, dd, J = 8.7, 2.3 Hz), 6.71 (1 H, d, J = 2.8 Hz), 6.85 (1 H, d, (J = 8.3 Hz)
参考例１９
Figure JPOXMLDOC01-appb-I000033
Reference Example 19
Figure JPOXMLDOC01-appb-I000033
ｔｅｒｔ－ブチル＝２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，９－ジアザスピロ（５．５）ウンデカン－９－カルボキシラート143mgを用いて参考例１４と同様の操作により、無色粉末状の２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，９－ジアザスピロ（５．５）ウンデカン－１－オンの塩酸塩112mgを得た。
1H NMR (DMSO-d6)δ 1.63 - 1.69 (2 H, m), 1.84 - 1.88 (4 H, m), 2.14 (2 H, ddd, J=14.1, 9.5, 3.9 Hz), 3.04 (2 H, ddd, J=12.8, 9.4, 3.4 Hz), 3.23 (2 H, ddd, J=12.6, 6.6, 4.1 Hz), 3.48 - 3.53 (2 H, m), 4.23 (4 H, s), 6.64 - 6.68 (1 H, m), 6.74 (1 H, d, J=2.3 Hz), 6.83 (1 H, d, J=8.7 Hz), 8.47 (1 H, br. s.) Reference using 143 mg of tert-butyl = 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxo-2,9-diazaspiro (5.5) undecane-9-carboxylate In the same manner as in Example 14, colorless powdery 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxo-2,9-diazaspiro (5.5) undecane-1 -112 mg of the hydrochloride of ON was obtained.
1H NMR (DMSO-d6) δ 1.63-1.69 (2 H, m), 1.84-1.88 (4 H, m), 2.14 (2 H, ddd, J = 14.1, 9.5, 3.9 Hz), 3.04 (2 H, ddd, J = 12.8, 9.4, 3.4 Hz), 3.23 (2 H, ddd, J = 12.6, 6.6, 4.1 Hz), 3.48-3.53 (2 H, m), 4.23 (4 H, s), 6.64-6.68 (1 H, m), 6.74 (1 H, d, J = 2.3 Hz), 6.83 (1 H, d, J = 8.7 Hz), 8.47 (1 H, br.s.)
参考例２０
Figure JPOXMLDOC01-appb-I000034
Reference Example 20
Figure JPOXMLDOC01-appb-I000034
２－（１，４－ジオキサスピロ（４．５）デカン－８－イリデン）エタノール837mgをクロロホルム20mLに溶解し、トリエチルアミン1mLを加えて氷冷し、メタンスルホニルクロリド0.53mLを加えた。室温にて１．５時間撹拌後、水20mLを加えて有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去して、黄色油状の８－（２－クロロエチリデン）－１，４－ジオキサスピロ（４．５）デカン1.26gを得た。
1H NMR (CHLOROFORM-d)δ 1.66 - 1.77 (4 H, m), 2.25 - 2.42 (4 H, m), 3.95 - 4.00 (4 H, m), 4.10 (2 H, d, J=8.0 Hz), 5.47 (1 H, tt, J=8.0, 1.3 Hz) 837 mg of 2- (1,4-dioxaspiro (4.5) decan-8-ylidene) ethanol was dissolved in 20 mL of chloroform, 1 mL of triethylamine was added and ice-cooled, and 0.53 mL of methanesulfonyl chloride was added. After stirring at room temperature for 1.5 hours, 20 mL of water was added to separate the organic layer. The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 8- (2-chloroethylidene) -1,4-dioxaspiro (4.5 ) 1.26 g of decane was obtained.
1H NMR (CHLOROFORM-d) δ 1.66-1.77 (4 H, m), 2.25-2.42 (4 H, m), 3.95-4.00 (4 H, m), 4.10 (2 H, d, J = 8.0 Hz) , 5.47 (1 H, tt, J = 8.0, 1.3 Hz)
参考例２１
Figure JPOXMLDOC01-appb-I000035
Reference Example 21
Figure JPOXMLDOC01-appb-I000035
７－フルオロ－１Ｈ－（１，５）－ナフチリジン－２－オン392mgをＮ，Ｎ－ジメチルホルムアミド10mLに懸濁し、６０％水素化ナトリウム116mgを加えて室温にて１．５時間撹拌した。２－（１，４－ジオキサスピロ（４．５）デカン－８－イル）エチル＝メタンスルホナート631mgのＮ，Ｎ－ジメチルホルムアミド5mL溶液を加え、室温にて３日間撹拌した。反応混合物に水45mL、酢酸エチル50mL及びトルエン10mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去して、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル：メタノール＝９：１］で精製して、淡黄色固体状の１－（２－（１，４－ジオキサスピロ（４．５）デカン－８－イル）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン108mgを得た。
1H NMR (CHLOROFORM-d)δ 1.36 - 1.43 (2 H, m), 1.48 - 1.56 (2 H, m), 1.57 - 1.67 (3 H, m), 1.79 (2 H, dd, J=14.4, 2.1 Hz), 1.85 - 1.90 (2 H, m), 3.93 - 3.98 (4 H, m), 4.20 - 4.24 (2 H, m), 6.86 (1 H, d, J=9.6 Hz), 7.31 (1 H, dd, J=10.1, 2.3 Hz), 7.87 (1 H, d, J=9.6 Hz), 8.42 (1 H, d, J=2.3 Hz) 392 mg of 7-fluoro-1H- (1,5) -naphthyridin-2-one was suspended in 10 mL of N, N-dimethylformamide, 116 mg of 60% sodium hydride was added, and the mixture was stirred at room temperature for 1.5 hours. A solution of 631 mg of 2- (1,4-dioxaspiro (4.5) decan-8-yl) ethyl methanesulfonate in 5 mL of N, N-dimethylformamide was added and stirred at room temperature for 3 days. To the reaction mixture, 45 mL of water, 50 mL of ethyl acetate and 10 mL of toluene were added, and the organic layer was separated. The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, 1- (2- (1,4-dioxaspiro (4.5) decan-8-yl) ethyl) -7-fluoro in the form of a pale yellow solid purified by eluent; ethyl acetate: methanol = 9: 1] 108 mg of -1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.36-1.43 (2 H, m), 1.48-1.56 (2 H, m), 1.57-1.67 (3 H, m), 1.79 (2 H, dd, J = 14.4, 2.1 Hz), 1.85-1.90 (2 H, m), 3.93-3.98 (4 H, m), 4.20-4.24 (2 H, m), 6.86 (1 H, d, J = 9.6 Hz), 7.31 (1 H , dd, J = 10.1, 2.3 Hz), 7.87 (1 H, d, J = 9.6 Hz), 8.42 (1 H, d, J = 2.3 Hz)
参考例２２
Figure JPOXMLDOC01-appb-I000036
Reference Example 22
Figure JPOXMLDOC01-appb-I000036
７－フルオロ－１Ｈ－（１，５）－ナフチリジン－２－オン350mgをＮ，Ｎ－ジメチルホルミアミド10mLに懸濁し、氷冷下６０％水素化ナトリウム102mgを加えて室温にて２時間撹拌した。８－（２－クロロエチリデン）－１，４－ジオキサスピロ（４．５）デカン559mgのＮ，Ｎ－ジメチルホルムアミド溶液3mLを加えて室温にて３日間撹拌した。反応混合物に水45mL、酢酸エチル50mL及びトルエン10mLを加えて有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去して、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル：メタノール＝９：１］で精製して、淡黄色固体状の１－（２－（１，４－ジオキサスピロ（４．５）デカン－８－イリデン）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン202mgを得た。
1H NMR (CHLOROFORM-d)δ 1.67 - 1.73 (2 H, m), 1.79 - 1.84 (2 H, m), 2.27 (2 H, t, J=6.4 Hz), 2.54 - 2.59 (2 H, m), 3.95 - 4.02 (4 H, m), 4.88 (2 H, d, J=6.4 Hz), 5.14 (1 H, t, J=6.6 Hz), 6.88 (1 H, d, J=10.1 Hz), 7.30 (1 H, dd, J=10.1, 2.3 Hz), 7.85 - 7.90 (1 H, m), 8.41 (1 H, d, J=2.3 Hz) 7-Fluoro-1H- (1,5) -naphthyridin-2-one (350 mg) is suspended in 10 mL of N, N-dimethylformamide, and 100 mg of 60% sodium hydride is added under ice cooling, followed by stirring at room temperature for 2 hours. did. 8- (2-Chloroethylidene) -1,4-dioxaspiro (4.5) decane (559 mg) in N, N-dimethylformamide solution (3 mL) was added, and the mixture was stirred at room temperature for 3 days. To the reaction mixture, 45 mL of water, 50 mL of ethyl acetate and 10 mL of toluene were added, and the organic layer was separated. The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, 1- (2- (1,4-dioxaspiro (4.5) decan-8-ylidene) ethyl) -7-fluoro as a pale yellow solid was purified by eluent; ethyl acetate: methanol = 9: 1]. 202 mg of -1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.67-1.73 (2 H, m), 1.79-1.84 (2 H, m), 2.27 (2 H, t, J = 6.4 Hz), 2.54-2.59 (2 H, m) , 3.95-4.02 (4 H, m), 4.88 (2 H, d, J = 6.4 Hz), 5.14 (1 H, t, J = 6.6 Hz), 6.88 (1 H, d, J = 10.1 Hz), 7.30 (1 H, dd, J = 10.1, 2.3 Hz), 7.85-7.90 (1 H, m), 8.41 (1 H, d, J = 2.3 Hz)
参考例２３
Figure JPOXMLDOC01-appb-I000037
Reference Example 23
Figure JPOXMLDOC01-appb-I000037
７－メトキシ－１Ｈ－（１，５）－ナフチリジン－２－オン869mg及び２－（１，４－ジオキサスピロ（４．５）デカン－８－イリデン）エチル＝メタンスルホナート1.43gを用いて参考例２１と同様の操作により、淡黄色固体状の１－（２－（１，４－ジオキサスピロ（４．５）デカン－８－イリデン）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン961mgを得た。
1H NMR (CHLOROFORM-d)δ 1.75 (4 H, dt, J=19.4, 6.8 Hz), 2.21 - 2.32 (2 H, m), 2.52 - 2.62 (2 H, m), 3.95 (3 H, s), 3.96 - 4.01 (4 H, m), 4.92 (2 H, d, J=6.2 Hz), 5.11 - 5.22 (1 H, m), 6.77 (1 H, d, J=9.7 Hz), 7.02 (1 H, d, J=2.2 Hz), 7.81 - 7.88 (1 H, m), 8.27 (1 H, d, J=2.2 Hz) Reference example using 869 mg of 7-methoxy-1H- (1,5) -naphthyridin-2-one and 1.43 g of 2- (1,4-dioxaspiro (4.5) decan-8-ylidene) ethyl methanesulfonate 1- (2- (1,4-dioxaspiro (4.5) decan-8-ylidene) ethyl) -7-methoxy-1H- (1,5) naphthyridine- 961 mg of 2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.75 (4 H, dt, J = 19.4, 6.8 Hz), 2.21-2.32 (2 H, m), 2.52-2.62 (2 H, m), 3.95 (3 H, s) , 3.96-4.01 (4 H, m), 4.92 (2 H, d, J = 6.2 Hz), 5.11-5.22 (1 H, m), 6.77 (1 H, d, J = 9.7 Hz), 7.02 (1 H, d, J = 2.2 Hz), 7.81-7.88 (1 H, m), 8.27 (1 H, d, J = 2.2 Hz)
参考例２４
Figure JPOXMLDOC01-appb-I000038
Reference Example 24
Figure JPOXMLDOC01-appb-I000038
１－（２－（１，４－ジオキサスピロ（４．５）デカン－８－イル）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン168mgをアセトン6mLに溶解し、トリフルオロメタンスルホン酸インジウム（ＩＩＩ）3mgを加え、室温にて２２時間、５０℃にて４８時間撹拌した。反応混合物を減圧下溶媒留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル：ヘキサン＝９５：５］で精製して、白色固体状の７－フルオロ－１－（２－（４－オキソシクロヘキシル）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン95mgを得た。
1H NMR (CHLOROFORM-d)δ 1.50 - 1.59 (2 H, m), 1.71 - 1.76 (2 H, m), 1.89 - 1.97 (1 H, m), 2.19 - 2.25 (2 H, m), 2.35 - 2.46 (4 H, m), 4.27 - 4.30 (2 H, m), 6.88 (1 H, d, J=9.6 Hz), 7.32 (1 H, dd, J=10.1, 2.3 Hz), 7.89 - 7.91 (1 H, m), 8.44 (1 H, d, J=2.3 Hz) 168 mg of 1- (2- (1,4-dioxaspiro (4.5) decan-8-yl) ethyl) -7-fluoro-1H- (1,5) naphthyridin-2-one is dissolved in 6 mL of acetone, and trifluoro 3 mg of indium (III) methanesulfonate was added and stirred at room temperature for 22 hours and at 50 ° C. for 48 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent; ethyl acetate: hexane = 95: 5] to give a white solid. 7-fluoro-1- (2- (4-oxocyclohexyl) ethyl) -1H- (1,5) naphthyridin-2-one in the form of 95 mg was obtained.
1H NMR (CHLOROFORM-d) δ 1.50-1.59 (2 H, m), 1.71-1.76 (2 H, m), 1.89-1.97 (1 H, m), 2.19-2.25 (2 H, m), 2.35- 2.46 (4 H, m), 4.27-4.30 (2 H, m), 6.88 (1 H, d, J = 9.6 Hz), 7.32 (1 H, dd, J = 10.1, 2.3 Hz), 7.89-7.91 ( 1 H, m), 8.44 (1 H, d, J = 2.3 Hz)
参考例２５
Figure JPOXMLDOC01-appb-I000039
Reference Example 25
Figure JPOXMLDOC01-appb-I000039
１－（２－（１，４－ジオキサスピロ（４．５）デカン－８－イリデン）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン200mgを用いて、参考例２４と同様の操作により白色固体状の７－フルオロ－１－（２－（４－オキソシクロヘキシリデン）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン95mgを得た。
1H NMR (CHLOROFORM-d)δ 2.41 - 2.46 (2 H, m), 2.50 - 2.54 (2 H, m), 2.56 (2 H, t, J=7.1 Hz), 2.82 (2 H, t, J=7.1 Hz), 4.92 (2 H, d, J=6.4 Hz), 5.36 (1 H, td, J=5.8, 1.1 Hz), 6.89 (1 H, d, J=10.1 Hz), 7.33 (1 H, dd, J=10.1, 1.8 Hz), 7.86 - 7.94 (1 H, m), 8.44 (1 H, d, J=1.8 Hz) Using 200 mg of 1- (2- (1,4-dioxaspiro (4.5) decan-8-ylidene) ethyl) -7-fluoro-1H- (1,5) naphthyridin-2-one, By the same operation, white solid 7-fluoro-1- (2- (4-oxocyclohexylidene) ethyl) -1H- (1,5) naphthyridin-2-one (95 mg) was obtained.
1H NMR (CHLOROFORM-d) δ 2.41-2.46 (2 H, m), 2.50-2.54 (2 H, m), 2.56 (2 H, t, J = 7.1 Hz), 2.82 (2 H, t, J = 7.1 Hz), 4.92 (2 H, d, J = 6.4 Hz), 5.36 (1 H, td, J = 5.8, 1.1 Hz), 6.89 (1 H, d, J = 10.1 Hz), 7.33 (1 H, dd, J = 10.1, 1.8 Hz), 7.86-7.94 (1 H, m), 8.44 (1 H, d, J = 1.8 Hz)
参考例２６
Figure JPOXMLDOC01-appb-I000040
Reference Example 26
Figure JPOXMLDOC01-appb-I000040
１－（２－（１，４－ジオキサスピロ（４．５）デカン－８－イリデン）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン950mgを用いて、参考例２４と同様の操作により黄白色固体状の７－メトキシ－１－（２－（４－オキソシクロヘキシリデン）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン280mgを得た。
1H NMR (CHLOROFORM-d)δ 2.37 - 2.60 (6 H, m), 2.77 - 2.88 (2 H, m), 3.97 (3 H, s), 4.94 (2 H, d, J=6.6 Hz), 5.33 - 5.44 (1 H, m), 6.77 (1 H, d, J=9.7 Hz), 7.03 (1 H, d, J=2.2 Hz), 7.86 (1 H, d, J=9.7), 8.30 (1 H, d, J=2.2 Hz) Using Reference Example 24 and 950 mg of 1- (2- (1,4-dioxaspiro (4.5) decan-8-ylidene) ethyl) -7-methoxy-1H- (1,5) naphthyridin-2-one By the same operation, 280 mg of 7-methoxy-1- (2- (4-oxocyclohexylidene) ethyl) -1H- (1,5) naphthyridin-2-one as a yellowish white solid was obtained.
1H NMR (CHLOROFORM-d) δ 2.37-2.60 (6 H, m), 2.77-2.88 (2 H, m), 3.97 (3 H, s), 4.94 (2 H, d, J = 6.6 Hz), 5.33 -5.44 (1 H, m), 6.77 (1 H, d, J = 9.7 Hz), 7.03 (1 H, d, J = 2.2 Hz), 7.86 (1 H, d, J = 9.7), 8.30 (1 (H, d, J = 2.2 Hz)
参考例２７
Figure JPOXMLDOC01-appb-I000041
Reference Example 27
Figure JPOXMLDOC01-appb-I000041
７－フルオロ－１－（２－（４－オキソシクロヘキシル）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン94mgをジメチルスルホキシド2mLに溶解し、トリメチルスルホニウムヨージド93mg、６０％水素化ナトリウム18mgを加え、５０℃で１時間撹拌した。反応混合物を氷冷し、水20mL及びジエチルエーテル20mLを加えて有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去して、白色固体状の７－フルオロ－１－（２－（１－オキサスピロ（２．５）オクタ－６－イル）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン73mgを得た。
1H NMR (CHLOROFORM-d)δ 0.82 - 0.91 (2 H, m), 1.19 - 1.36 (4 H, m), 1.40 (1 H, dt, J=13.2, 2.6 Hz), 1.55 - 1.63 (1 H, m), 1.65 - 1.71 (2 H, m), 1.85 - 1.95 (2 H, m), 2.02 - 2.07 (1 H, m), 4.25 (2 H, dt, J=12.2, 8.1 Hz), 6.87 (1 H, d, J=9.6 Hz), 7.30 - 7.33 (1 H, m), 7.88 (1 H, dd, J=9.9, 1.6 Hz), 8.43 (1 H, t, J=2.3 Hz) 94 mg of 7-fluoro-1- (2- (4-oxocyclohexyl) ethyl) -1H- (1,5) naphthyridin-2-one was dissolved in 2 mL of dimethyl sulfoxide, 93 mg of trimethylsulfonium iodide, 60% sodium hydride 18 mg was added and stirred at 50 ° C. for 1 hour. The reaction mixture was ice-cooled, water (20 mL) and diethyl ether (20 mL) were added, and the organic layer was separated. The organic layer was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give white solid 7-fluoro-1- (2- (1-oxaspiro (2.5 73 mg of) oct-6-yl) ethyl) -1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 0.82-0.91 (2 H, m), 1.19-1.36 (4 H, m), 1.40 (1 H, dt, J = 13.2, 2.6 Hz), 1.55-1.63 (1 H, m), 1.65-1.71 (2 H, m), 1.85-1.95 (2 H, m), 2.02-2.07 (1 H, m), 4.25 (2 H, dt, J = 12.2, 8.1 Hz), 6.87 ( 1 H, d, J = 9.6 Hz), 7.30-7.33 (1 H, m), 7.88 (1 H, dd, J = 9.9, 1.6 Hz), 8.43 (1 H, t, J = 2.3 Hz)
参考例２８
Figure JPOXMLDOC01-appb-I000042
Reference Example 28
Figure JPOXMLDOC01-appb-I000042
７－フルオロ－１－（２－（４－オキソシクロヘキシリデン）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン70mgを用いて、参考例２７と同様の操作により、淡黄色固体状の７－フルオロ－１－（２－（１－オキサスピロ（２．５）オクタ－６－イリデン）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン51mgを得た。
1H NMR (CHLOROFORM-d)δ 1.52 - 1.57 (1 H, m), 1.64 - 1.69 (1 H, m), 1.74 - 1.79 (1 H, m), 1.84 - 1.90 (1 H, m), 2.21 - 2.26 (1 H, m), 2.39 - 2.45 (1 H, m), 2.55 - 2.62 (1 H, m), 2.65 - 2.68 (1 H, m), 2.70 (1 H, d, J=5.0 Hz), 2.72 - 2.74 (1 H, m), 4.81 (1 H, dd, J=15.6, 6.0 Hz), 5.01 (1 H, dd, J=15.1, 6.9 Hz), 5.21 (1 H, t, J=6.4 Hz), 6.89 (1 H, d, J=9.6 Hz), 7.33 (1 H, dd, J=10.1, 1.8 Hz), 7.87 - 7.91 (1 H, m), 8.42 (1 H, d, J=1.8 Hz) Using 70 mg of 7-fluoro-1- (2- (4-oxocyclohexylidene) ethyl) -1H- (1,5) naphthyridin-2-one in the same manner as in Reference Example 27, a pale yellow solid was obtained. Thus, 51 mg of 7-fluoro-1- (2- (1-oxaspiro (2.5) oct-6-ylidene) ethyl) -1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.52-1.57 (1 H, m), 1.64-1.69 (1 H, m), 1.74-1.79 (1 H, m), 1.84-1.90 (1 H, m), 2.21- 2.26 (1 H, m), 2.39-2.45 (1 H, m), 2.55-2.62 (1 H, m), 2.65-2.68 (1 H, m), 2.70 (1 H, d, J = 5.0 Hz) , 2.72-2.74 (1 H, m), 4.81 (1 H, dd, J = 15.6, 6.0 Hz), 5.01 (1 H, dd, J = 15.1, 6.9 Hz), 5.21 (1 H, t, J = 6.4 Hz), 6.89 (1 H, d, J = 9.6 Hz), 7.33 (1 H, dd, J = 10.1, 1.8 Hz), 7.87-7.91 (1 H, m), 8.42 (1 H, d, J = 1.8 Hz)
参考例２９
Figure JPOXMLDOC01-appb-I000043
Reference Example 29
Figure JPOXMLDOC01-appb-I000043
７－フルオロ－１－（２－（１－オキサスピロ（２．５）オクタ－６－イル）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン70mg及び２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イルアミン35mgを９０％エタノール2mLに溶解し、８５℃にて２３時間撹拌した。反応混合物を減圧下溶媒留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア株式会社、Chromatorex-NH、溶離液；酢酸エチル：ヘキサン＝７：３］で精製して１－（２－（４－（（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イルアミノ）メチル）－４－ヒドロキシシクロヘキシル）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン54mg（ジアステレオマーＡ：24mg、黄色固体状物質、ジアステレオマーＢ：30mg、黄色油状物質）を得た。
ジアステレオマーＡ
1H NMR (CHLOROFORM-d)δ 1.35 - 1.85 (11 H, m), 3.02 (2 H, s), 4.14 - 4.31 (6 H, m), 6.18 - 6.27 (2 H, m), 6.65 - 6.75 (1 H, m), 6.86 (1 H, d, J=9.7 Hz), 7.33 (1 H, dd, J=9.4, 2.2 Hz), 7.82 - 7.92 (1 H, m), 8.42 (1 H, d, J=2.2 Hz)
ジアステレオマーＢ
1H NMR (CHLOROFORM-d)δ 1.12 - 1.99 (11 H, m), 3.13 (2 H, s), 4.15 - 4.27 (6 H, m), 6.18 - 6.27 (2 H, m), 6.66 - 6.74 (1 H, m), 6.87 (1 H, d, J=10.1 Hz), 7.31 (1 H, dd, J=9.9, 2.0 Hz), 7.82 - 7.92 (1 H, m), 8.43 (1 H, d, J=2.0 Hz) 7-Fluoro-1- (2- (1-oxaspiro (2.5) oct-6-yl) ethyl) -1H- (1,5) naphthyridin-2-one 70 mg and 2,3-dihydrobenzo (1, 4) 35 mg of dioxin-6-ylamine was dissolved in 2 mL of 90% ethanol and stirred at 85 ° C. for 23 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Ltd., Chromatorex-NH, eluent: ethyl acetate: hexane = 7: 3] to give 1- (2- (4-((2,3-dihydrobenzo (1,4) dioxin-6-ylamino) methyl) -4-hydroxycyclohexyl) ethyl) -7-fluoro-1H- (1,5) naphthyridine-2 -54 mg (diastereomer A: 24 mg, yellow solid substance, diastereomer B: 30 mg, yellow oily substance) were obtained.
Diastereomer A
1H NMR (CHLOROFORM-d) δ 1.35-1.85 (11 H, m), 3.02 (2 H, s), 4.14-4.31 (6 H, m), 6.18-6.27 (2 H, m), 6.65-6.75 ( 1 H, m), 6.86 (1 H, d, J = 9.7 Hz), 7.33 (1 H, dd, J = 9.4, 2.2 Hz), 7.82-7.92 (1 H, m), 8.42 (1 H, d , J = 2.2 Hz)
Diastereomer B
1H NMR (CHLOROFORM-d) δ 1.12-1.99 (11 H, m), 3.13 (2 H, s), 4.15-4.27 (6 H, m), 6.18-6.27 (2 H, m), 6.66-6.74 ( 1 H, m), 6.87 (1 H, d, J = 10.1 Hz), 7.31 (1 H, dd, J = 9.9, 2.0 Hz), 7.82-7.92 (1 H, m), 8.43 (1 H, d , J = 2.0 Hz)
参考例３０
Figure JPOXMLDOC01-appb-I000044
Reference Example 30
Figure JPOXMLDOC01-appb-I000044
７－フルオロ－１－（２－（１－オキサスピロ（２．５）オクタ－６－イリデン）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン50mg及び２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イルアミン28mgを用いて参考例２９と同様の操作により、黄色油状の１－（２－（４－（（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イルアミノ）メチル）－４－ヒドロキシシクロヘキシリデン）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン43mgを得た。
1H NMR (CHLOROFORM-d)δ 1.47 - 1.62 (2 H, m), 1.77 - 1.82 (1 H, m), 1.90 - 1.95 (1 H, m), 2.05 - 2.09 (1 H, m), 2.42 - 2.51 (2 H, m), 2.65 - 2.70 (1 H, m), 3.08 (2 H, d, J=2.8 Hz), 4.18 - 4.20 (2 H, m), 4.22 - 4.24 (2 H, m), 4.74 - 4.79 (1 H, m), 5.00 (1 H, dd, J=15.6, 6.4 Hz), 5.13 (1 H, t, J=6.6 Hz), 6.25 - 6.32 (2 H, m), 6.72 (1 H, d, J=8.7 Hz), 6.88 (1 H, d, J=9.6 Hz), 7.32 (1 H, dd, J=10.1, 2.3 Hz), 7.88 (1 H, d, J=9.6 Hz), 8.42 (1 H, d, J=2.3 Hz) 7-fluoro-1- (2- (1-oxaspiro (2.5) oct-6-ylidene) ethyl) -1H- (1,5) naphthyridin-2-one 50 mg and 2,3-dihydrobenzo (1, 4) 1- (2- (4-((2,3-dihydrobenzo (1,4) dioxin-6-ylamino) in the form of a yellow oil) was obtained in the same manner as in Reference Example 29 using 28 mg of dioxin-6-ylamine. 43 mg of methyl) -4-hydroxycyclohexylidene) ethyl) -7-fluoro-1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.47-1.62 (2 H, m), 1.77-1.82 (1 H, m), 1.90-1.95 (1 H, m), 2.05-2.09 (1 H, m), 2.42- 2.51 (2 H, m), 2.65-2.70 (1 H, m), 3.08 (2 H, d, J = 2.8 Hz), 4.18-4.20 (2 H, m), 4.22-4.24 (2 H, m) , 4.74-4.79 (1 H, m), 5.00 (1 H, dd, J = 15.6, 6.4 Hz), 5.13 (1 H, t, J = 6.6 Hz), 6.25-6.32 (2 H, m), 6.72 (1 H, d, J = 8.7 Hz), 6.88 (1 H, d, J = 9.6 Hz), 7.32 (1 H, dd, J = 10.1, 2.3 Hz), 7.88 (1 H, d, J = 9.6 Hz), 8.42 (1 H, d, J = 2.3 Hz)
参考例３１
Figure JPOXMLDOC01-appb-I000045
Reference Example 31
Figure JPOXMLDOC01-appb-I000045
７－メトキシ－１－（２－（１－オキサスピロ（２．５）オクタ－６－イリデン）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン110mg及び２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イルアミン59mgを用いて参考例３０と同様の操作により、黄色油状の１－（２－（４－（（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イルアミノ）メチル）－４－ヒドロキシシクロヘキシリデン）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン145mgを得た。
1H NMR (CHLOROFORM-d)δ 1.51 (1 H, td, J=12.7, 4.4 Hz), 1.59 (1 H, td, J=12.7, 4.4 Hz), 1.75 - 1.81 (1 H, m), 1.89 - 1.95 (1 H, m), 2.05 - 2.11 (1 H, m), 2.40 - 2.50 (2 H, m), 2.69 (1 H, dt, J=13.5, 4.0 Hz), 3.02 - 3.09 (2 H, m), 3.95 (3 H, s), 4.18 (2 H, td, J=3.7, 1.8 Hz), 4.22 (2 H, td, J=3.8, 2.1 Hz), 4.74 (1 H, dd, J=15.4, 6.6 Hz), 5.09 (1 H, dd, J=15.6, 6.0 Hz), 5.14 - 5.18 (1 H, m), 6.19 - 6.23 (1 H, m), 6.24 (1 H, s), 6.70 (1 H, d, J=8.7 Hz), 6.76 (1 H, d, J=9.6 Hz), 7.04 (1 H, d, J=2.3 Hz), 7.85 (1 H, d, J=9.6 Hz), 8.27 (1 H, d, J=2.3 Hz) 7-methoxy-1- (2- (1-oxaspiro (2.5) oct-6-ylidene) ethyl) -1H- (1,5) naphthyridin-2-one 110 mg and 2,3-dihydrobenzo (1, 4) 1- (2- (4-((2,3-dihydrobenzo (1,4) dioxin-6-ylamino) in the form of a yellow oil) was prepared in the same manner as in Reference Example 30 using 59 mg of dioxin-6-ylamine. 145 mg of methyl) -4-hydroxycyclohexylidene) ethyl) -7-methoxy-1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.51 (1 H, td, J = 12.7, 4.4 Hz), 1.59 (1 H, td, J = 12.7, 4.4 Hz), 1.75-1.81 (1 H, m), 1.89- 1.95 (1 H, m), 2.05-2.11 (1 H, m), 2.40-2.50 (2 H, m), 2.69 (1 H, dt, J = 13.5, 4.0 Hz), 3.02-3.09 (2 H, m), 3.95 (3 H, s), 4.18 (2 H, td, J = 3.7, 1.8 Hz), 4.22 (2 H, td, J = 3.8, 2.1 Hz), 4.74 (1 H, dd, J = 15.4, 6.6 Hz), 5.09 (1 H, dd, J = 15.6, 6.0 Hz), 5.14-5.18 (1 H, m), 6.19-6.23 (1 H, m), 6.24 (1 H, s), 6.70 (1 H, d, J = 8.7 Hz), 6.76 (1 H, d, J = 9.6 Hz), 7.04 (1 H, d, J = 2.3 Hz), 7.85 (1 H, d, J = 9.6 Hz) , 8.27 (1 H, d, J = 2.3 Hz)
参考例３２
Figure JPOXMLDOC01-appb-I000046
Reference Example 32
Figure JPOXMLDOC01-appb-I000046
７－フルオロ－１－（２－（１－オキサスピロ（２．５）オクタ－６－イリデン）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン61mg及び２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イルアミン31mgを用いて参考例３１と同様の操作により、無色泡状の１－（２－（４－（（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イルアミノ）メチル）－４－ヒドロキシシクロヘキシリデン）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン3mgを得た。
1H NMR (CHLOROFORM-d)δ 1.37 (1 H, td, J=12.4, 4.6 Hz), 1.47 (1 H, td, J=12.5, 4.4 Hz), 1.74 - 1.81 (1 H, m), 1.89 - 1.96 (1 H, m), 2.04 (1 H, dt, J=13.4, 4.3 Hz), 2.44 - 2.55 (2 H, m), 2.59 - 2.66 (1 H, m), 3.29 - 3.33 (2 H, m), 4.17 - 4.21 (2 H, m), 4.27 - 4.31 (2 H, m), 4.43 (1 H, br. s.), 4.73 (1 H, dd, J=15.1, 5.5 Hz), 5.02 - 5.12 (2 H, m), 5.99 (1 H, s), 6.88 (1 H, d, J=10.1 Hz), 7.33 (1 H, dd, J=10.1, 2.3 Hz), 7.64 (1 H, s), 7.88 (1 H, d, J=10.1 Hz), 8.41 (1 H, d, J=2.3 Hz) 7-fluoro-1- (2- (1-oxaspiro (2.5) oct-6-ylidene) ethyl) -1H- (1,5) naphthyridin-2-one 61 mg and 2,3-dihydro- (1, 4) 1- (2- (4-((2,3-dihydro- (1) of colorless foam) was prepared by the same procedure as in Reference Example 31 using 31 mg of dioxino (2,3-c) pyridin-7-ylamine. , 4) Dioxino (2,3-c) pyridin-7-ylamino) methyl) -4-hydroxycyclohexylidene) ethyl) -7-fluoro-1H- (1,5) naphthyridin-2-one 3 mg was obtained. .
1H NMR (CHLOROFORM-d) δ 1.37 (1 H, td, J = 12.4, 4.6 Hz), 1.47 (1 H, td, J = 12.5, 4.4 Hz), 1.74-1.81 (1 H, m), 1.89- 1.96 (1 H, m), 2.04 (1 H, dt, J = 13.4, 4.3 Hz), 2.44-2.55 (2 H, m), 2.59-2.66 (1 H, m), 3.29-3.33 (2 H, m), 4.17-4.21 (2 H, m), 4.27-4.31 (2 H, m), 4.43 (1 H, br.s.), 4.73 (1 H, dd, J = 15.1, 5.5 Hz), 5.02 -5.12 (2 H, m), 5.99 (1 H, s), 6.88 (1 H, d, J = 10.1 Hz), 7.33 (1 H, dd, J = 10.1, 2.3 Hz), 7.64 (1 H, s), 7.88 (1 H, d, J = 10.1 Hz), 8.41 (1 H, d, J = 2.3 Hz)
参考例３３
Figure JPOXMLDOC01-appb-I000047
Reference Example 33
Figure JPOXMLDOC01-appb-I000047
７－フルオロ－１－（２－（１－オキサスピロ（２．５）オクタ－６－イリデン）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン200mg及び６－アミノ－４Ｈ－ベンゾ（１，４）オキサジン－３－オン120mgを用いて、参考例２９と同様の操作により、淡黄色泡状の６－（（４－（２－（７－フルオロ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）エチリデン）－１－ヒドロキシシクロヘキシルメチル）アミノ）－４Ｈ－ベンゾ（１，４）オキサジン－３－オン30mgを得た。
1H NMR (CHLOROFORM-d)δ 1.36 - 2.90 (8 H, m), 3.07 (2 H, s), 4.51 (2 H, s), 4.67 - 5.21 (3 H, m), 6.19 (1 H, s), 6.29 (1 H, d, J=8.8 Hz), 6.80 (1 H, d, J=8.8 Hz), 6.89 (1 H, d, J=9.7 Hz), 7.33 (1 H, dd, J=10.3, 2.4 Hz), 7.89 (1 H, d, J=9.7 Hz), 8.43 (1 H, d, J=2.4 Hz), 8.80 (1 H, s) 7-Fluoro-1- (2- (1-oxaspiro (2.5) oct-6-ylidene) ethyl) -1H- (1,5) naphthyridin-2-one 200 mg and 6-amino-4H-benzo (1 , 4) Using 120 mg of oxazin-3-one, 6-((4- (2- (7-fluoro-2-oxo-2H- (1, 5) 30 mg of naphthyridin-1-yl) ethylidene) -1-hydroxycyclohexylmethyl) amino) -4H-benzo (1,4) oxazin-3-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.36-2.90 (8 H, m), 3.07 (2 H, s), 4.51 (2 H, s), 4.67-5.21 (3 H, m), 6.19 (1 H, s ), 6.29 (1 H, d, J = 8.8 Hz), 6.80 (1 H, d, J = 8.8 Hz), 6.89 (1 H, d, J = 9.7 Hz), 7.33 (1 H, dd, J = 10.3, 2.4 Hz), 7.89 (1 H, d, J = 9.7 Hz), 8.43 (1 H, d, J = 2.4 Hz), 8.80 (1 H, s)
参考例３４
Figure JPOXMLDOC01-appb-I000048
Reference Example 34
Figure JPOXMLDOC01-appb-I000048
７－フルオロ－１－（２－（１－オキサスピロ（２．５）オクタ－６－イリデン）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン194mg及び３－フルオロ－４－メチルアニリン99mgを用いて、参考例２９と同様の操作により、淡黄色固体状の７－フルオロ－１－（２－（４－（（３－フルオロ－４－メチルフェニルアミノ）メチル）－４－ヒドロキシシクロヘキシリデン）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン132mgを得た。
1H NMR (DMSO-d6)δ 1.40 (1 H, td, J=12.4, 4.6 Hz), 1.47 (1 H, td, J=12.6, 4.1 Hz), 1.58 - 1.63 (1 H, m), 1.71 - 1.76 (1 H, m), 1.97 (1 H, dt, J=13.2, 4.2 Hz), 2.04 (3 H, s), 2.28 - 2.35 (2 H, m), 2.64 (1 H, dt, J=13.6, 4.2 Hz), 2.95 (2 H, d, J=6.0 Hz), 4.44 (1 H, s), 4.80 - 4.86 (1 H, m), 4.88 - 4.94 (1 H, m), 5.07 (1 H, t, J=6.6 Hz), 5.42 (1 H, t, J=5.7 Hz), 6.36 - 6.42 (2 H, m), 6.84 (1 H, d, J=9.6 Hz), 6.89 (1 H, t, J=8.9 Hz), 7.76 (1 H, dd, J=11.0, 2.3 Hz), 7.95 (1 H, d, J=9.6 Hz), 8.57 (1 H, d, J=2.3 Hz) 7-Fluoro-1- (2- (1-oxaspiro (2.5) oct-6-ylidene) ethyl) -1H- (1,5) naphthyridin-2-one 194 mg and 3-fluoro-4-methylaniline 99 mg Was used in the same manner as in Reference Example 29 to prepare a pale yellow solid 7-fluoro-1- (2- (4-((3-fluoro-4-methylphenylamino) methyl) -4-hydroxycyclohexylene. Den) ethyl) -1H- (1,5) naphthyridin-2-one 132 mg was obtained.
1H NMR (DMSO-d6) δ 1.40 (1 H, td, J = 12.4, 4.6 Hz), 1.47 (1 H, td, J = 12.6, 4.1 Hz), 1.58-1.63 (1 H, m), 1.71- 1.76 (1 H, m), 1.97 (1 H, dt, J = 13.2, 4.2 Hz), 2.04 (3 H, s), 2.28-2.35 (2 H, m), 2.64 (1 H, dt, J = 13.6, 4.2 Hz), 2.95 (2 H, d, J = 6.0 Hz), 4.44 (1 H, s), 4.80-4.86 (1 H, m), 4.88-4.94 (1 H, m), 5.07 (1 H, t, J = 6.6 Hz), 5.42 (1 H, t, J = 5.7 Hz), 6.36-6.42 (2 H, m), 6.84 (1 H, d, J = 9.6 Hz), 6.89 (1 H , t, J = 8.9 Hz), 7.76 (1 H, dd, J = 11.0, 2.3 Hz), 7.95 (1 H, d, J = 9.6 Hz), 8.57 (1 H, d, J = 2.3 Hz)
参考例３５
Figure JPOXMLDOC01-appb-I000049
Reference Example 35
Figure JPOXMLDOC01-appb-I000049
（７－フルオロ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒドの塩酸塩280mgをクロロホルム10mLに懸濁し、トリエチルアミン322μLを加えて溶解させた。室温にて１．５時間撹拌した後、ｔｅｒｔ－ブチル＝３，９－ジアザスピロ（５．５）ウンデカン－３－カルボキシラート320mgのクロロホルム溶液5mLを加え、さらに室温にて１６時間撹拌した。反応混合物を氷冷し、トリアセトキシ水素化ホウ素ナトリウム515mgを加え、室温に戻して３．５時間撹拌した。反応液に水5mLを加え、反応混合物を減圧下溶媒留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル］で精製して、淡黄色油状のｔｅｒｔ－ブチル＝９－（２－（７－フルオロ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）エチル）－３，９－ジアザスピロ（５．５）ウンデカン－３－カルボキシラート468mgを得た。
1H NMR (CHLOROFORM-d)δ 1.38 - 1.48 (13 H, m), 1.49 - 1.55 (4 H, m), 2.54 (4 H, t, J=5.5 Hz), 2.61 - 2.68 (2 H, m), 3.33 - 3.39 (4 H, m), 4.32 (2 H, t, J=7.1 Hz), 6.86 (1 H, d, J=10.1 Hz), 7.54 (1 H, dd, J=10.5, 2.3 Hz), 7.86 - 7.90 (1 H, m), 8.42 (1 H, d, J=2.3 Hz) 280 mg of the hydrochloride salt of (7-fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde was suspended in 10 mL of chloroform and dissolved by adding 322 μL of triethylamine. After stirring at room temperature for 1.5 hours, 5 mL of a chloroform solution of 320 mg of tert-butyl = 3,9-diazaspiro (5.5) undecane-3-carboxylate was added, and the mixture was further stirred at room temperature for 16 hours. The reaction mixture was ice-cooled, 515 mg of sodium triacetoxyborohydride was added, and the mixture was warmed to room temperature and stirred for 3.5 hours. 5 mL of water was added to the reaction solution, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: ethyl acetate] Pale yellow oily tert-butyl = 9- (2- (7-fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -3,9-diazaspiro (5.5) undecane- 468 mg of 3-carboxylate was obtained.
1H NMR (CHLOROFORM-d) δ 1.38-1.48 (13 H, m), 1.49-1.55 (4 H, m), 2.54 (4 H, t, J = 5.5 Hz), 2.61-2.68 (2 H, m) , 3.33-3.39 (4 H, m), 4.32 (2 H, t, J = 7.1 Hz), 6.86 (1 H, d, J = 10.1 Hz), 7.54 (1 H, dd, J = 10.5, 2.3 Hz ), 7.86-7.90 (1 H, m), 8.42 (1 H, d, J = 2.3 Hz)
参考例３６
Figure JPOXMLDOC01-appb-I000050
Reference Example 36
Figure JPOXMLDOC01-appb-I000050
ｔｅｒｔ－ブチル＝９－（２－（７－フルオロ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）エチル）－３，９－ジアザスピロ（５．５）ウンデカン－３－カルボキシラート438mgを用いて、参考例１３と同様の操作により、１－（２－（３，９－ジアザスピロ（５．５）ウンデカン－３－イル）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オンの塩酸塩318mgを得た。
1H NMR (DMSO-d6)δ 1.50 - 1.58 (2 H, m), 1.69 (2 H, td, J=13.9, 3.9 Hz), 1.78 - 1.85 (2 H, m), 1.90 (2 H, d, J=15.6 Hz), 3.04 (2 H, d, J=6.9 Hz), 3.10 - 3.20 (2 H, m), 3.29 - 3.38 (2 H, m), 3.49 (2 H, d, J=11.9 Hz), 4.47 - 4.84 (2 H, m), 6.88 (1 H, d, J=9.2 Hz), 8.00 (1 H, d, J=9.2 Hz), 8.41 (1 H, dd, J=11.0, 1.8 Hz), 8.62 (1 H, d, J=1.8 Hz), 8.83 (2 H, br. s.) tert-Butyl = 9- (2- (7-Fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -3,9-diazaspiro (5.5) undecane-3-carboxylate 1- (2- (3,9-diazaspiro (5.5) undecan-3-yl) ethyl) -7-fluoro-1H- (1,5) was prepared in the same manner as in Reference Example 13 using 438 mg. 318 mg of naphthyridin-2-one hydrochloride was obtained.
1H NMR (DMSO-d6) δ 1.50-1.58 (2 H, m), 1.69 (2 H, td, J = 13.9, 3.9 Hz), 1.78-1.85 (2 H, m), 1.90 (2 H, d, J = 15.6 Hz), 3.04 (2 H, d, J = 6.9 Hz), 3.10-3.20 (2 H, m), 3.29-3.38 (2 H, m), 3.49 (2 H, d, J = 11.9 Hz ), 4.47-4.84 (2 H, m), 6.88 (1 H, d, J = 9.2 Hz), 8.00 (1 H, d, J = 9.2 Hz), 8.41 (1 H, dd, J = 11.0, 1.8 Hz), 8.62 (1 H, d, J = 1.8 Hz), 8.83 (2 H, br.s.)
参考例３７
Figure JPOXMLDOC01-appb-I000051
Reference Example 37
Figure JPOXMLDOC01-appb-I000051
（７－フルオロ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒドの塩酸塩100mg及びｔｅｒｔ－ブチル＝２，７－ジアザスピロ（４．４）ノナン－２－カルボキシラート93mgを用いて、参考例３５と同様の操作により、ｔｅｒｔ－ブチル＝７－（２－（７－フルオロ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）エチル）－２，７－ジアザスピロ（４．４）ノナン－２－カルボキシラート105mgを得た。
1H NMR (METHANOL-d4)δ 1.45 (9 H, s), 1.75 - 1.96 (4 H, m), 2.56 - 2.87 (4 H, m), 3.18 - 3.23 (1 H, m), 3.27 (1 H, br. s.), 3.33 - 3.36 (4 H, m), 4.39 - 4.46 (2 H, m), 6.87 (1 H, d, J=9.6 Hz), 7.97 (2 H, m), 8.49 (1 H, d, J=2.3 Hz) 100 mg of (7-fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde hydrochloride and 93 mg of tert-butyl = 2,7-diazaspiro (4.4) nonane-2-carboxylate In the same manner as in Reference Example 35, tert-butyl = 7- (2- (7-fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -2,7- 105 mg of diazaspiro (4.4) nonane-2-carboxylate was obtained.
1H NMR (METHANOL-d4) δ 1.45 (9 H, s), 1.75-1.96 (4 H, m), 2.56-2.87 (4 H, m), 3.18-3.23 (1 H, m), 3.27 (1 H , br. s.), 3.33-3.36 (4 H, m), 4.39-4.46 (2 H, m), 6.87 (1 H, d, J = 9.6 Hz), 7.97 (2 H, m), 8.49 ( (1 H, d, J = 2.3 Hz)
参考例３８
Figure JPOXMLDOC01-appb-I000052
Reference Example 38
Figure JPOXMLDOC01-appb-I000052
ｔｅｒｔ－ブチル＝７－（２－（７－フルオロ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）エチル）－２，７－ジアザスピロ（４．４）ノナン－２－カルボキシラート105mgを用いて、参考例１３の操作と同様にして、無色固体状の１－（２－（２，７－ジアザスピロ（４．４）ノナ－２－イル）エチル）－７－フルオロ－１Ｈ－（１，５）－ナフチリジン－２－オンの塩酸塩92mgを得た。
1H NMR (DMSO-d6)δ 1.92 - 2.30 (4 H, m), 3.18 - 3.35 (6 H, m), 3.45 (2 H, br. s.), 3.68 - 3.86 (2 H, m), 4.52 - 4.63 (2 H, m), 6.88 (1 H, d, J=9.6 Hz), 8.00 (1 H, d, J=9.6 Hz), 8.29 - 8.38 (1 H, m), 8.62 (1 H, d, J=2.3 Hz) tert-butyl = 7- (2- (7-fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -2,7-diazaspiro (4.4) nonane-2-carboxylate Using 105 mg, in the same manner as in Reference Example 13, colorless solid 1- (2- (2,7-diazaspiro (4.4) non-2-yl) ethyl) -7-fluoro-1H— 92 mg of hydrochloride of (1,5) -naphthyridin-2-one was obtained.
1H NMR (DMSO-d6) δ 1.92-2.30 (4 H, m), 3.18-3.35 (6 H, m), 3.45 (2 H, br.s.), 3.68-3.86 (2 H, m), 4.52 -4.63 (2 H, m), 6.88 (1 H, d, J = 9.6 Hz), 8.00 (1 H, d, J = 9.6 Hz), 8.29-8.38 (1 H, m), 8.62 (1 H, d, J = 2.3 Hz)
参考例３９
Figure JPOXMLDOC01-appb-I000053
Reference Example 39
Figure JPOXMLDOC01-appb-I000053
（７－フルオロ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒドの塩酸塩200mg及びｔｅｒｔ－ブチル＝１Ｈ－スピロ（イソキノリン－４，４’－ピペリジン）－２（３Ｈ）－カルボキシラート279mgをクロロホルム5mLに懸濁させ、トリエチルアミン0.29mLを加えて溶解させた。酢酸68μLを加え、５０℃にて６時間撹拌した。反応混合物を氷冷し、トリアセトキシ水素化ホウ素ナトリウム368mgを加え、室温にて２１時間撹拌した。反応混合物を減圧下溶媒留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア株式会社、Chromatorex-NH、溶離液；酢酸エチル：ヘキサン＝１：１］で精製して、淡黄色油状物を得た。これを２－プロパノール50mLに懸濁し、2 mol/L塩酸の２－プロパノール溶液10mLを加え、５０℃にて２１時間撹拌した。反応混合物を減圧下溶媒留去して、白色固体状の１－（２－（２，３－ジヒドロ－１Ｈ－スピロ（イソキノリン－４，４’－ピペリジン）－１’－イル）エチル）－７－フルオロ－（１，５）－ナフチリジン－２（１Ｈ）－オンの塩酸塩270mgを得た。
1H NMR (DMSO-d6)δ 2.15 (2 H, d, J=14.7 Hz), 2.52 - 2.59 (2 H, m), 3.31 - 3.45 (4 H, m), 3.58 - 3.69 (4 H, m), 4.26 (2 H, t, J=4.1 Hz), 4.63 - 4.73 (2 H, m), 6.90 (1 H, d, J=9.6 Hz), 7.24 - 7.29 (1 H, m), 7.30 - 7.34 (1 H, m), 7.43 (1 H, t, J=7.3 Hz), 7.56 (1 H, d, J=7.8 Hz), 8.01 (1 H, d, J=9.6 Hz), 8.41 (1 H, dd, J=11.0, 1.8 Hz), 8.63 (1 H, d, J=1.8 Hz), 11.63 (1 H, br. s.) 200 mg of (7-fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde hydrochloride and tert-butyl = 1H-spiro (isoquinoline-4,4′-piperidine) -2 (3H) -279 mg of carboxylate was suspended in 5 mL of chloroform and dissolved by adding 0.29 mL of triethylamine. Acetic acid (68 μL) was added and the mixture was stirred at 50 ° C. for 6 hours. The reaction mixture was ice-cooled, sodium triacetoxyborohydride (368 mg) was added, and the mixture was stirred at room temperature for 21 hr. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Ltd., Chromatorex-NH, eluent: ethyl acetate: hexane = 1: 1] A yellow oil was obtained. This was suspended in 50 mL of 2-propanol, 10 mL of 2-propanol solution of 2 mol / L hydrochloric acid was added, and the mixture was stirred at 50 ° C. for 21 hours. The reaction mixture was evaporated under reduced pressure to give 1- (2- (2,3-dihydro-1H-spiro (isoquinolin-4,4′-piperidin) -1′-yl) ethyl) -7 as a white solid. 270 mg of hydrochloride of -fluoro- (1,5) -naphthyridin-2 (1H) -one was obtained.
1H NMR (DMSO-d6) δ 2.15 (2 H, d, J = 14.7 Hz), 2.52-2.59 (2 H, m), 3.31-3.45 (4 H, m), 3.58-3.69 (4 H, m) , 4.26 (2 H, t, J = 4.1 Hz), 4.63-4.73 (2 H, m), 6.90 (1 H, d, J = 9.6 Hz), 7.24-7.29 (1 H, m), 7.30-7.34 (1 H, m), 7.43 (1 H, t, J = 7.3 Hz), 7.56 (1 H, d, J = 7.8 Hz), 8.01 (1 H, d, J = 9.6 Hz), 8.41 (1 H , dd, J = 11.0, 1.8 Hz), 8.63 (1 H, d, J = 1.8 Hz), 11.63 (1 H, br.s.)
参考例４０
Figure JPOXMLDOC01-appb-I000054
Reference Example 40
Figure JPOXMLDOC01-appb-I000054
（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒド211mg及びｔｅｒｔ－ブチル＝２，８－ジアザスピロ（４．５）デカン－２－カルボキシラート279mgをクロロホルム10mL及びメタノール0.5mLに溶解し、室温にて１８時間撹拌した。トリアセトキシ水素化ホウ素ナトリウム431mgを加えて２．５時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液10mLを加え、有機層を分取した。有機層を減圧下溶媒留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア株式会社、Chromatorex-NH、溶離液；酢酸エチル：ヘキサン＝４：１］で精製して、無色油状のｔｅｒｔ－ブチル＝８－（２－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）エチル）－２，８－ジアザスピロ（４．５）デカン－２－カルボキシラート290mgを得た。
1H NMR (CHLOROFORM-d)δ 1.46 (9 H, s), 1.55 - 1.64 (3 H, m), 1.64 - 1.74 (4 H, m), 2.49 (2 H, br. s.), 2.59 - 2.69 (3 H, m), 3.12 (1 H, s), 3.20 (1 H, s), 3.35 (1 H, t, J=7.1 Hz), 3.40 (1 H, t, J=6.9 Hz), 3.98 (3 H, s), 4.37 (2 H, br. s.), 6.75 (1 H, d, J=9.2 Hz), 7.21 (1 H, d, J=1.8 Hz), 7.84 (1 H, d, J=9.2 Hz), 8.28 (1 H, d, J=1.8 Hz) (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde (211 mg) and tert-butyl = 2,8-diazaspiro (4.5) decane-2-carboxylate (279 mg) Dissolved in 0.5 mL of methanol and stirred at room temperature for 18 hours. 431 mg of sodium triacetoxyborohydride was added and stirred for 2.5 hours. To the reaction mixture, 10 mL of a saturated aqueous sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Ltd., Chromatorex-NH, eluent: ethyl acetate: hexane = 4: 1] and colorless. Oily tert-butyl 8- (2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -2,8-diazaspiro (4.5) decane-2- 290 mg of carboxylate was obtained.
1H NMR (CHLOROFORM-d) δ 1.46 (9 H, s), 1.55-1.64 (3 H, m), 1.64-1.74 (4 H, m), 2.49 (2 H, br.s.), 2.59-2.69 (3 H, m), 3.12 (1 H, s), 3.20 (1 H, s), 3.35 (1 H, t, J = 7.1 Hz), 3.40 (1 H, t, J = 6.9 Hz), 3.98 (3 H, s), 4.37 (2 H, br.s.), 6.75 (1 H, d, J = 9.2 Hz), 7.21 (1 H, d, J = 1.8 Hz), 7.84 (1 H, d , J = 9.2 Hz), 8.28 (1 H, d, J = 1.8 Hz)
参考例４１
Figure JPOXMLDOC01-appb-I000055
Reference Example 41
Figure JPOXMLDOC01-appb-I000055
ｔｅｒｔ－ブチル＝８－（２－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）エチル）－２，８－ジアザスピロ（４．５）デカン－２－カルボキシラート290mgを１，４－ジオキサン5mLに溶解し、4 mol/L塩酸の１，４－ジオキサン溶液5mLを加えて、室温で４時間撹拌した。反応混合物を減圧下溶媒留去して、黄白色固体状の１－（２－（２，８－ジアザスピロ（４．５）デカン－８－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オンの塩酸塩400mgを得た。
1H NMR (DMSO-d6)δ 1.78 - 1.97 (6 H, m), 2.99 (1 H, t, J=5.7 Hz), 3.08 - 3.15 (1 H, m), 3.18 (1 H, t, J=5.7 Hz), 3.20 - 3.35 (5 H, m), 3.58 - 3.63 (2 H, m), 4.07 (3 H, s), 4.69 - 4.73 (2 H, m), 6.71 (1 H, d, J=9.6 Hz), 7.72 (1 H, d, J=2.3 Hz), 7.94 (1 H, d, J=9.6 Hz), 8.33 (1 H, d, J=2.3 Hz) tert-Butyl = 8- (2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -2,8-diazaspiro (4.5) decane-2-carboxylate 290 mg was dissolved in 5 mL of 1,4-dioxane, 5 mL of 1,4-dioxane solution of 4 mol / L hydrochloric acid was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to give 1- (2- (2,8-diazaspiro (4.5) decan-8-yl) ethyl) -7-methoxy-1H- (1, 5) 400 mg of naphthyridin-2-one hydrochloride was obtained.
1H NMR (DMSO-d6) δ 1.78-1.97 (6 H, m), 2.99 (1 H, t, J = 5.7 Hz), 3.08-3.15 (1 H, m), 3.18 (1 H, t, J = 5.7 Hz), 3.20-3.35 (5 H, m), 3.58-3.63 (2 H, m), 4.07 (3 H, s), 4.69-4.73 (2 H, m), 6.71 (1 H, d, J = 9.6 Hz), 7.72 (1 H, d, J = 2.3 Hz), 7.94 (1 H, d, J = 9.6 Hz), 8.33 (1 H, d, J = 2.3 Hz)
参考例４２
Figure JPOXMLDOC01-appb-I000056
Reference Example 42
Figure JPOXMLDOC01-appb-I000056
７－メトキシ－１Ｈ－（１，５）－ナフチリジン－２－オン5.06gをＮ，Ｎ－ジメチルホルムアミド50mLに懸濁し、６０％水素化ナトリウム2.51gを加え、窒素雰囲気下８５℃にて２５分撹拌した。（３－ブロモプロポキシ）－ｔｅｒｔ－ブチルジメチルシラン20.6mLのＮ，Ｎ－ジメチルホルミアミド溶液30mLを加え、８５℃にて１５時間撹拌した。反応混合物を室温に戻し、水150mL、酢酸エチル70mL及びトルエン30mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液50mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去して、褐色油状の１－（３－（ｔｅｒｔ－ブチルジメチルシラニルオキシ）プロピル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン4.08gを得た。
1H NMR (CHLOROFORM-d)δ 0.10 (6 H, s), 0.94 (9 H, s), 1.91 - 1.98 (2 H, m), 3.79 (2 H, t, J=5.5 Hz), 3.96 (3 H, s), 4.31 - 4.38 (2 H, m), 6.76 (1 H, d, J=7.8 Hz), 7.28 (1 H, br. s.), 7.88 (1 H, br. s.), 8.30 (1 H, br. s.) Suspend 5.06 g of 7-methoxy-1H- (1,5) -naphthyridin-2-one in 50 mL of N, N-dimethylformamide, add 2.51 g of 60% sodium hydride, and continue at 85 ° C. for 25 minutes under a nitrogen atmosphere. Stir. (3-Bromopropoxy) -tert-butyldimethylsilane (20.6 mL) in N, N-dimethylformamide solution (30 mL) was added, and the mixture was stirred at 85 ° C. for 15 hours. The reaction mixture was returned to room temperature, 150 mL of water, 70 mL of ethyl acetate and 30 mL of toluene were added, and the organic layer was separated. The organic layer was washed with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1- (3- (tert-butyldimethylsilanyloxy) propyl) -7 as a brown oil. 4.08 g of -methoxy-1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 0.10 (6 H, s), 0.94 (9 H, s), 1.91-1.98 (2 H, m), 3.79 (2 H, t, J = 5.5 Hz), 3.96 (3 H, s), 4.31-4.38 (2 H, m), 6.76 (1 H, d, J = 7.8 Hz), 7.28 (1 H, br.s.), 7.88 (1 H, br.s.), 8.30 (1 H, br. S.)
参考例４３
Reference Example 43
１－（３－（ｔｅｒｔ－ブチルジメチルシラニルオキシ）プロピル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン3.989gをテトラヒドロフラン40mLに溶解し、1mol/Lのフッ化テトラ-n-ブチルアンモニウムのテトラヒドロフラン溶液22.9mLを加えて、室温にて１４時間撹拌した。反応混合物を減圧下溶媒留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル：メタノール＝９：１］で精製して、白色固体状の１－（３－ヒドロキシプロピル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン2.47gを得た。
1H NMR (CHLOROFORM-d)δ 1.92 - 2.06 (2 H, m), 3.49 - 3.63 (3 H, m), 3.99 (3 H, s), 4.38 - 4.48 (2 H, m), 6.80 (1 H, d, J=9.7 Hz), 7.19 (1 H, d, J=2.2 Hz), 7.92 (1 H, d, J=9.7 Hz), 8.33 (1 H, d, J=2.2 Hz) 3.989 g of 1- (3- (tert-butyldimethylsilanyloxy) propyl) -7-methoxy-1H- (1,5) naphthyridin-2-one was dissolved in 40 mL of tetrahydrofuran, and 1 mol / L of tetrafluorofluoride- 22.9 mL of a tetrahydrofuran solution of n-butylammonium was added and stirred at room temperature for 14 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent; ethyl acetate: methanol = 9: 1] to give a white solid. 1.47 g of 1- (3-hydroxypropyl) -7-methoxy-1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.92-2.06 (2 H, m), 3.49-3.63 (3 H, m), 3.99 (3 H, s), 4.38-4.48 (2 H, m), 6.80 (1 H , d, J = 9.7 Hz), 7.19 (1 H, d, J = 2.2 Hz), 7.92 (1 H, d, J = 9.7 Hz), 8.33 (1 H, d, J = 2.2 Hz)
参考例４４
Figure JPOXMLDOC01-appb-I000058
Reference Example 44
Figure JPOXMLDOC01-appb-I000058
１－（３－ヒドロキシプロピル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン500mgをクロロホルム30mLに溶解し、１，１，１－トリアセトキシ－１，１－ジヒドロ－１，２－ベンズヨードキソール－３（１Ｈ）－オン1.21gを加えて、室温にて６．５時間撹拌した。反応混合物を減圧下溶媒留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル：メタノール＝９５：５］で精製して黄色油状の３－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）プロピオンアルデヒド562mgを得た。
1H NMR (CHLOROFORM-d)δ 2.98 (2 H, td, J=7.0, 0.9 Hz), 3.99 (3 H, s), 4.55 (2 H, t, J=6.8 Hz), 6.75 (1 H, d, J=10.1 Hz), 7.21 (1 H, d, J=2.2 Hz), 7.83 - 7.91 (1 H, m), 8.29 (1 H, d, J=2.2 Hz), 9.87 - 9.91 (1 H, m) 500 mg of 1- (3-hydroxypropyl) -7-methoxy-1H- (1,5) naphthyridin-2-one is dissolved in 30 mL of chloroform, and 1,1,1-triacetoxy-1,1-dihydro-1, 1.21 g of 2-benziodoxol-3 (1H) -one was added and stirred at room temperature for 6.5 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent; ethyl acetate: methanol = 95: 5] There was obtained 562 mg of 3- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) propionaldehyde.
1H NMR (CHLOROFORM-d) δ 2.98 (2 H, td, J = 7.0, 0.9 Hz), 3.99 (3 H, s), 4.55 (2 H, t, J = 6.8 Hz), 6.75 (1 H, d , J = 10.1 Hz), 7.21 (1 H, d, J = 2.2 Hz), 7.83-7.91 (1 H, m), 8.29 (1 H, d, J = 2.2 Hz), 9.87-9.91 (1 H, m)
参考例４５
Figure JPOXMLDOC01-appb-I000059
Reference Example 45
Figure JPOXMLDOC01-appb-I000059
ｔｅｒｔ－ブチル＝３－オキソ－２，８－ジアザスピロ（４．５）デカン－８－カルボキシラート75mgをＮ，Ｎ－ジメチルホルムアミド2mLに溶解し、６０％水素化ナトリウム14mgを加えた。さらに７－クロロメチル－２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン60mgのＮ，Ｎ－ジメチルホルミアミド2mL－テトラヒドロフラン2mL溶液を加え、７０℃にて１５時間撹拌した。反応混合物を室温に戻し、水10mL、酢酸エチル10mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去して、褐色油状の２－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イルメチル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－８－カルボキシラート108mgを得た。これを酢酸エチル2mLに溶解し、4 mol/L塩酸の酢酸エチル溶液4mLを加えて、室温にて３時間撹拌した。反応混合物を減圧下溶媒留去して、褐色固体状の２－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イルメチル）－２，８－ジアザスピロ（４．５）デカン－３－オンの塩酸塩129mgを得た。
1H NMR (DMSO-d6)δ 1.71 - 1.79 (4 H, m), 2.38 (2 H, s), 2.96 - 3.07 (4 H, m), 3.29 (2 H, s), 4.56 - 4.62 (4 H, m), 4.63 (2 H, s), 7.33 (1 H, s), 8.56 (1 H, s) 75 mg of tert-butyl = 3-oxo-2,8-diazaspiro (4.5) decane-8-carboxylate was dissolved in 2 mL of N, N-dimethylformamide, and 14 mg of 60% sodium hydride was added. Further, a solution of 60 mg of 7-chloromethyl-2,3-dihydro- (1,4) dioxyno (2,3-c) pyridine in 2 mL of N, N-dimethylformamide-2 mL of tetrahydrofuran was added, and the mixture was stirred at 70 ° C. for 15 hours. Stir. The reaction mixture was returned to room temperature, 10 mL of water and 10 mL of ethyl acetate were added, and the organic layer was separated. The organic layer was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2- (2,3-dihydro- (1,4) dioxyno (2, 3-c) 108 mg of pyridin-7-ylmethyl) -3-oxo-2,8-diazaspiro (4.5) decane-8-carboxylate was obtained. This was dissolved in 2 mL of ethyl acetate, 4 mL of 4 mol / L hydrochloric acid in ethyl acetate was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated under reduced pressure to give 2- (2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) -2,8-diazaspiro ( 4.5) 129 mg of decan-3-one hydrochloride was obtained.
1H NMR (DMSO-d6) δ 1.71-1.79 (4 H, m), 2.38 (2 H, s), 2.96-3.07 (4 H, m), 3.29 (2 H, s), 4.56-4.62 (4 H , m), 4.63 (2 H, s), 7.33 (1 H, s), 8.56 (1 H, s)
参考例４６
Figure JPOXMLDOC01-appb-I000060
Reference Example 46
Figure JPOXMLDOC01-appb-I000060
ｔｅｒｔ－ブチル＝５’－オキソ－８－アザスピロ（ビシクロ（３．２．１）オクタン－３，３’－ピロリジン）－８－カルボキシラート177mg及び６－ヨード－２，３－ジヒドロベンゾ（１，４）ジオキシン165mgを用いて、参考例１４と同様の操作により、ｔｅｒｔ－ブチル＝１’－（２，３－ジヒドロベンゾ（ｂ）（１，４）ジオキシン－６－イル）－５’－オキソ－８－アザスピロ（ビシクロ（３．２．１）オクタン－３，３’－ピロリジン）－８－カルボキシラート240mgを得た。
1H NMR (CHLOROFORM-d)δ 1.46 (9 H, s), 1.72 - 2.08 (8 H, m), 2.73 - 2.80 (2 H, m), 3.34 - 3.57 (2 H, m), 4.15 - 4.37 (6 H, m), 6.83 (1 H, d, J=9.2 Hz), 6.93 - 6.99 (1 H, m), 7.07 (1 H, d, J=2.3 Hz) tert-Butyl = 5′-oxo-8-azaspiro (bicyclo (3.2.1) octane-3,3′-pyrrolidine) -8-carboxylate 177 mg and 6-iodo-2,3-dihydrobenzo (1, 4) tert-Butyl = 1 ′-(2,3-dihydrobenzo (b) (1,4) dioxin-6-yl) -5′-oxo using 165 mg of dioxin in the same manner as in Reference Example 14 240 mg of -8-azaspiro (bicyclo (3.2.1) octane-3,3′-pyrrolidine) -8-carboxylate was obtained.
1H NMR (CHLOROFORM-d) δ 1.46 (9 H, s), 1.72-2.08 (8 H, m), 2.73-2.80 (2 H, m), 3.34-3.57 (2 H, m), 4.15-4.37 ( 6 H, m), 6.83 (1 H, d, J = 9.2 Hz), 6.93-6.99 (1 H, m), 7.07 (1 H, d, J = 2.3 Hz)
参考例４７
Figure JPOXMLDOC01-appb-I000061
Reference Example 47
Figure JPOXMLDOC01-appb-I000061
ｔｅｒｔ－ブチル＝１’－（２，３－ジヒドロベンゾ（ｂ）（１，４）ジオキシン－６－イル）－５’－オキソ－８－アザスピロ（ビシクロ（３．２．１）オクタン－３，３’－ピロリジン）－８－カルボキシラート240mgを用いて、参考例１５と同様の操作により、１’－（２，３－ジヒドロベンゾ（ｂ）（１，４）ジオキシン－６－イル）－８－アザスピロ（ビシクロ（３．２．１）オクタン－３，３’－ピロリジン）－５’－オン181mgを得た。
1H NMR (CHLOROFORM-d)δ 1.77 - 1.91 (8 H, m), 2.72 (2 H, s), 3.47 (2 H, s), 3.58 - 3.63 (2 H, m), 4.17 - 4.29 (4 H, m), 6.83 (1 H, d, J=8.7 Hz), 6.99 (1 H, dd, J=8.7, 2.3 Hz), 7.08 (1 H, d, J=2.3 Hz) tert-Butyl = 1 ′-(2,3-dihydrobenzo (b) (1,4) dioxin-6-yl) -5′-oxo-8-azaspiro (bicyclo (3.2.1) octane-3, 1 ′-(2,3-dihydrobenzo (b) (1,4) dioxin-6-yl) -8 was prepared in the same manner as in Reference Example 15 using 3 mg of 3′-pyrrolidine) -8-carboxylate. -181 mg of azaspiro (bicyclo (3.2.1) octane-3,3'-pyrrolidin) -5'-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.77-1.91 (8 H, m), 2.72 (2 H, s), 3.47 (2 H, s), 3.58-3.63 (2 H, m), 4.17-4.29 (4 H , m), 6.83 (1 H, d, J = 8.7 Hz), 6.99 (1 H, dd, J = 8.7, 2.3 Hz), 7.08 (1 H, d, J = 2.3 Hz)
参考例４８
Figure JPOXMLDOC01-appb-I000062
Reference Example 48
Figure JPOXMLDOC01-appb-I000062
ベンジル＝１－オキサ－６－アザスピロ（２．５）オクタン－６－カルボキシラート488mg及び２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イルアミン200mgを用いて、参考例２９と同様の操作により、無色油状のベンジル＝４－（（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イルアミノ）メチル）－４－ヒドロキシピペリジン－１－カルボキシラート51mgを得た。
1H NMR (CHLOROFORM-d)δ 1.42 (2 H, br. s.), 1.65 (2 H, br. s.), 3.28 (4 H, br. s.), 3.88 - 4.02 (2 H, m), 4.17 - 4.19 (2 H, m), 4.27 - 4.30 (2 H, m), 4.43 - 4.51 (1 H, m), 5.13 (2 H, s), 5.99 (1 H, s), 7.29 - 7.38 (5 H, m), 7.61 (1 H, s) With 488 mg benzyl = 1-oxa-6-azaspiro (2.5) octane-6-carboxylate and 200 mg 2,3-dihydro- (1,4) dioxino (2,3-c) pyridin-7-ylamine In the same manner as in Reference Example 29, colorless oily benzyl 4-((2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-ylamino) methyl) -4-hydroxy 51 mg of piperidine-1-carboxylate was obtained.
1H NMR (CHLOROFORM-d) δ 1.42 (2 H, br. S.), 1.65 (2 H, br. S.), 3.28 (4 H, br. S.), 3.88-4.02 (2 H, m) , 4.17-4.19 (2 H, m), 4.27-4.30 (2 H, m), 4.43-4.51 (1 H, m), 5.13 (2 H, s), 5.99 (1 H, s), 7.29-7.38 (5 H, m), 7.61 (1 H, s)
参考例４９
Figure JPOXMLDOC01-appb-I000063
Reference Example 49
Figure JPOXMLDOC01-appb-I000063
ベンジル＝４－（（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イルアミノ）メチル）－４－ヒドロキシピペリジン－１－カルボキシラート51mgをクロロホルム2mLに溶解し、トリエチルアミン0.05mL及び炭酸ビス(トリクロロメチル)38mgを加えて、窒素雰囲気下室温にて２時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液3mL及びクロロホルム5mLを加えて、有機層を分取した。有機層を飽和塩化ナトリウム水溶液2mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去して、黄色固体状のベンジル＝３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－カルボキシラート63mgを得た。
1H NMR (CHLOROFORM-d)δ 1.78 (2 H, br. s.), 1.97 (2 H, br. s.), 3.39 - 3.51 (2 H, m), 3.88 - 3.99 (4 H, m), 4.25 - 4.28 (2 H, m), 4.32 - 4.35 (2 H, m), 5.15 (2 H, s), 7.31 - 7.39 (5 H, m), 7.75 (1 H, s), 7.86 (1 H, s) Benzyl = 4-((2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-ylamino) methyl) -4-hydroxypiperidine-1-carboxylate 51 mg was dissolved in 2 mL of chloroform. , 0.05 mL of triethylamine and 38 mg of bis (trichloromethyl) carbonate were added, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (3 mL) and chloroform (5 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with 2 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain benzyl 3- (2,3-dihydro- (1,4) dioxyno as a yellow solid. 63 mg of (2,3-c) pyridin-7-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decane-8-carboxylate was obtained.
1H NMR (CHLOROFORM-d) δ 1.78 (2 H, br.s.), 1.97 (2 H, br. S.), 3.39-3.51 (2 H, m), 3.88-3.99 (4 H, m), 4.25-4.28 (2 H, m), 4.32-4.35 (2 H, m), 5.15 (2 H, s), 7.31-7.39 (5 H, m), 7.75 (1 H, s), 7.86 (1 H , s)
参考例５０
Figure JPOXMLDOC01-appb-I000064
Reference Example 50
Figure JPOXMLDOC01-appb-I000064
ベンジル＝３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－カルボキシラート63mgをエタノール3mLに溶解し、7.5%パラジウム炭素22mgを加え、水素雰囲気下４０℃で６時間撹拌した。不溶物を濾取し、濾液を減圧下溶媒留去して、白色固体状の３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン36mgを得た。
1H NMR (CHLOROFORM-d)δ 2.12 (2 H, d, J=13.8 Hz), 2.24 - 2.31 (2 H, m), 3.27 - 3.33 (2 H, m), 3.34 - 3.40 (2 H, m), 3.99 (2 H, s), 4.25 - 4.28 (2 H, m), 4.33 - 4.35 (2 H, m), 7.70 (1 H, s), 7.86 (1 H, s) Benzyl = 3- (2,3-dihydro- (1,4) dioxino (2,3-c) pyridin-7-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decane -8-Carboxylate (63 mg) was dissolved in ethanol (3 mL), 7.5% palladium carbon (22 mg) was added, and the mixture was stirred at 40 ° C. for 6 hours under hydrogen atmosphere. Insoluble matter was filtered off, and the filtrate was evaporated under reduced pressure to give 3- (2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-yl)-as a white solid. 36 mg of 1-oxa-3,8-diazaspiro (4.5) decan-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 2.12 (2 H, d, J = 13.8 Hz), 2.24-2.31 (2 H, m), 3.27-3.33 (2 H, m), 3.34-3.40 (2 H, m) , 3.99 (2 H, s), 4.25-4.28 (2 H, m), 4.33-4.35 (2 H, m), 7.70 (1 H, s), 7.86 (1 H, s)
参考例５１
Figure JPOXMLDOC01-appb-I000065
Reference Example 51
Figure JPOXMLDOC01-appb-I000065
７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン5.06gを用いて、参考例４２と同様の操作により、淡黄色固体状の１－（３－（ｔｅｒｔ－ブチルジメチルシラニルオキシ）プロピル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン1.23gを得た。
1H NMR (CHLOROFORM-d)δ 0.11 (6 H, s), 0.96 (9 H, s), 1.87 - 1.99 (2 H, m), 3.70 - 3.77 (2 H, m), 4.27 - 4.36 (2 H, m), 6.86 (1 H, d, J=10.1 Hz), 7.68 - 7.76 (1 H, m), 7.85 - 7.92 (1 H, m), 8.40 - 8.42 (1 H, m) Using 5.06 g of 7-fluoro-1H- (1,5) naphthyridin-2-one, the same operation as in Reference Example 42 was carried out to give 1- (3- (tert-butyldimethylsilanyloxy) as a pale yellow solid. Propyl) -7-fluoro-1H- (1,5) naphthyridin-2-one (1.23 g) was obtained.
1H NMR (CHLOROFORM-d) δ 0.11 (6 H, s), 0.96 (9 H, s), 1.87-1.99 (2 H, m), 3.70-3.77 (2 H, m), 4.27-4.36 (2 H , m), 6.86 (1 H, d, J = 10.1 Hz), 7.68-7.76 (1 H, m), 7.85-7.92 (1 H, m), 8.40-8.42 (1 H, m)
参考例５２
Figure JPOXMLDOC01-appb-I000066
Reference Example 52
Figure JPOXMLDOC01-appb-I000066
１－（３－（ｔｅｒｔ－ブチルジメチルシラニルオキシ）プロピル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン1.20gを用いて、参考例４３と同様の操作により、淡黄色固体状の１－（３－ヒドロキシプロピル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン0.70gを得た。
1H NMR (CHLOROFORM-d)δ 1.92 - 2.03 (2 H, m), 3.58 (2 H, br. s.), 4.40 (2 H, t, J=6.2 Hz), 6.92 (1 H, d, J=9.6 Hz), 7.51 (1 H, dd, J=9.9, 2.3 Hz), 7.95 (1 H, d, J=9.6 Hz), 8.47 (1 H, d, J=2.3 Hz) The procedure of Reference Example 43 was repeated using 1.20 g of 1- (3- (tert-butyldimethylsilanyloxy) propyl) -7-fluoro-1H- (1,5) naphthyridin-2-one. 0.70 g of solid 1- (3-hydroxypropyl) -7-fluoro-1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.92-2.03 (2 H, m), 3.58 (2 H, br.s.), 4.40 (2 H, t, J = 6.2 Hz), 6.92 (1 H, d, J = 9.6 Hz), 7.51 (1 H, dd, J = 9.9, 2.3 Hz), 7.95 (1 H, d, J = 9.6 Hz), 8.47 (1 H, d, J = 2.3 Hz)
参考例５３
Figure JPOXMLDOC01-appb-I000067
Reference Example 53
Figure JPOXMLDOC01-appb-I000067
１－（３－ヒドロキシプロピル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン142mgを用いて、参考例４４と同様の操作により、無色固体状の３－（７－フルオロ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）プロピオンアルデヒド158mgを得た。
1H NMR (CHLOROFORM-d)δ 2.95 - 3.00 (2 H, m), 4.51 (2 H, t, J=7.1 Hz), 6.87 (1 H, d, J=9.6 Hz), 7.50 (1 H, dd, J=10.1, 2.3 Hz), 7.90 - 7.93 (1 H, m), 8.45 (1 H, d, J=2.3 Hz), 9.88 (1 H, s) Using 142 mg of 1- (3-hydroxypropyl) -7-fluoro-1H- (1,5) naphthyridin-2-one in the same manner as in Reference Example 44, colorless solid 3- (7-fluoro- 158 mg of 2-oxo-2H- (1,5) naphthyridin-1-yl) propionaldehyde was obtained.
1H NMR (CHLOROFORM-d) δ 2.95-3.00 (2 H, m), 4.51 (2 H, t, J = 7.1 Hz), 6.87 (1 H, d, J = 9.6 Hz), 7.50 (1 H, dd , J = 10.1, 2.3 Hz), 7.90-7.93 (1 H, m), 8.45 (1 H, d, J = 2.3 Hz), 9.88 (1 H, s)
参考例５４
Figure JPOXMLDOC01-appb-I000068
Reference Example 54
Figure JPOXMLDOC01-appb-I000068
３－メトキシ－５Ｈ－ピリド（２，３－ｂ）ピラジン－６－オン980mgをジメチルスルホキシド15mLに懸濁し、ブロモ酢酸ｔｅｒｔ－ブチル0.86mL及びリン酸カリウム1.23gを加え、室温にて一晩撹拌した。反応混合物に水100mLを加え酢酸エチル100mLで２回抽出した。有機層を飽和食塩水100mLで洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル：メタノール＝１：１］で精製して淡黄色固体状のｔｅｒｔ－ブチル＝（２－（３－メトキシ－６－オキソ－６Ｈ－ピリド（２，３－ｂ）ピラジン－５－イル）アセタート1.21gを得た。
1H NMR (CHLOROFORM-d)δ 1.49 (9 H, s), 4.02 (3 H, s), 5.08 (2 H, s), 6.80 (1 H, d, J=10.1 Hz), 7.89 (1 H, d, J=10.1 Hz), 8.12 (1 H, s) Suspend 980 mg of 3-methoxy-5H-pyrido (2,3-b) pyrazin-6-one in 15 mL of dimethyl sulfoxide, add 0.86 mL of tert-butyl bromoacetate and 1.23 g of potassium phosphate, and stir overnight at room temperature. did. 100 mL of water was added to the reaction mixture, and the mixture was extracted twice with 100 mL of ethyl acetate. The organic layer was washed with 100 mL of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent; ethyl acetate: methanol = 1: 1] to give a pale yellow solid tert-butyl = (2- ( 1.21 g of 3-methoxy-6-oxo-6H-pyrido (2,3-b) pyrazin-5-yl) acetate was obtained.
1H NMR (CHLOROFORM-d) δ 1.49 (9 H, s), 4.02 (3 H, s), 5.08 (2 H, s), 6.80 (1 H, d, J = 10.1 Hz), 7.89 (1 H, d, J = 10.1 Hz), 8.12 (1 H, s)
参考例５５
Figure JPOXMLDOC01-appb-I000069
Reference Example 55
Figure JPOXMLDOC01-appb-I000069
ｔｅｒｔ－ブチル＝（２－（３－メトキシ－６－オキソ－６Ｈ－ピリド（２，３－ｂ）ピラジン－５－イル）アセタート980mgを酢酸エチル5mLに溶解し、4mol/L塩酸の酢酸エチル溶液10mLを加え、室温にて２０時間撹拌した。不溶物を濾取し、酢酸エチル50mLで洗浄後、乾燥して無色固体状の（２－（３－メトキシ－６－オキソ－６Ｈ－ピリド（２，３－ｂ）ピラジン－５－イル）酢酸の塩酸塩504mgを得た。
1H NMR (DMSO-d6)δ 3.99 (3 H, s), 5.00 (2 H, s), 6.77 (1 H, d, J=9.7 Hz), 8.02 (1 H, d, J=9.7 Hz), 8.27 (1 H, s) tert-Butyl = (2- (3-methoxy-6-oxo-6H-pyrido (2,3-b) pyrazin-5-yl) acetate (980 mg) was dissolved in ethyl acetate (5 mL), and 4 mol / L hydrochloric acid in ethyl acetate 10 mL was added, and the mixture was stirred at room temperature for 20 hours, the insoluble material was collected by filtration, washed with 50 mL of ethyl acetate, and dried to give (2- (3-methoxy-6-oxo-6H-pyrido (2 , 3-b) Pyrazin-5-yl) acetic acid hydrochloride 504 mg was obtained.
1H NMR (DMSO-d6) δ 3.99 (3 H, s), 5.00 (2 H, s), 6.77 (1 H, d, J = 9.7 Hz), 8.02 (1 H, d, J = 9.7 Hz), 8.27 (1 H, s)
参考例５６
Figure JPOXMLDOC01-appb-I000070
Reference Example 56
Figure JPOXMLDOC01-appb-I000070
ｔｅｒｔ－ブチル＝１－オキサ－６－アザスピロ（２．５）オクタン－６－カルボキシラート210mg及び２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｂ）ピリジン－６－アミン150mgを用いて、参考例２９と同様の操作により、褐色油状のｔｅｒｔ－ブチル＝４－（（（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｂ）ピリジン－６－イル）アミノ）メチル）－４－ヒドロキシピペリジン－１－カルボキシラート294mgを得た。
1H NMR (CHLOROFORM-d)δ 1.49 (9 H, s), 1.60 - 1.67 (2 H, m), 2.04 (2 H, s), 3.20 (2 H, d, J=5.0 Hz), 3.29 - 3.34 (2 H, m), 4.13 - 4.18 (2 H, m), 4.34 - 4.39 (2 H, m), 4.40 - 4.46 (1 H, m), 4.57 (1 H, s), 6.02 - 6.09 (1 H, m), 7.00 - 7.04 (1 H, m) tert-butyl = 1-oxa-6-azaspiro (2.5) octane-6-carboxylate 210 mg and 2,3-dihydro- (1,4) dioxyno (2,3-b) pyridin-6-amine 150 mg In the same manner as in Reference Example 29, tert-butyl 4-(((2,3-dihydro- (1,4) dioxyno (2,3-b) pyridin-6-yl) amino in the form of a brown oil was used. ) 294 mg of methyl) -4-hydroxypiperidine-1-carboxylate were obtained.
1H NMR (CHLOROFORM-d) δ 1.49 (9 H, s), 1.60-1.67 (2 H, m), 2.04 (2 H, s), 3.20 (2 H, d, J = 5.0 Hz), 3.29-3.34 (2 H, m), 4.13-4.18 (2 H, m), 4.34-4.39 (2 H, m), 4.40-4.46 (1 H, m), 4.57 (1 H, s), 6.02-6.09 (1 H, m), 7.00-7.04 (1 H, m)
参考例５７
Figure JPOXMLDOC01-appb-I000071
Reference Example 57
Figure JPOXMLDOC01-appb-I000071
ｔｅｒｔ－ブチル＝４－（（（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｂ）ピリジン－６－イル）アミノ）メチル）－４－ヒドロキシピペリジン－１－カルボキシラート289mgを用いて、参考例４９と同様の操作により、無色油状のｔｅｒｔ－ブチル＝３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｂ）ピリジン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－カルボキシラート161mgを得た。
1H NMR (CHLOROFORM-d)δ 1.49 (9 H, s), 1.74 (2 H, d, J=1.4 Hz), 1.90 - 1.97 (2 H, m), 3.38 (2 H, br. s.), 3.73 - 3.82 (2 H, m), 3.94 (2 H, s), 4.21 - 4.25 (2 H, m), 4.41 - 4.44 (2 H, m), 7.23 - 7.26 (1 H, m), 7.76 (1 H, d, J=8.7 Hz) tert-Butyl = 4-(((2,3-dihydro- (1,4) dioxyno (2,3-b) pyridin-6-yl) amino) methyl) -4-hydroxypiperidine-1-carboxylate 289 mg Using the same procedure as in Reference Example 49, colorless oily tert-butyl = 3- (2,3-dihydro- (1,4) dioxyno (2,3-b) pyridin-6-yl) -2- 161 mg of oxo-1-oxa-3,8-diazaspiro (4.5) decane-8-carboxylate was obtained.
1H NMR (CHLOROFORM-d) δ 1.49 (9 H, s), 1.74 (2 H, d, J = 1.4 Hz), 1.90-1.97 (2 H, m), 3.38 (2 H, br.s.), 3.73-3.82 (2 H, m), 3.94 (2 H, s), 4.21-4.25 (2 H, m), 4.41-4.44 (2 H, m), 7.23-7.26 (1 H, m), 7.76 ( (1 H, d, J = 8.7 Hz)
参考例５８
Figure JPOXMLDOC01-appb-I000072
Reference Example 58
Figure JPOXMLDOC01-appb-I000072
ｔｅｒｔ－ブチル＝３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｂ）ピリジン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－カルボキシラート153mgをクロロホルム2mLに溶解し、トリフルオロ酢酸1mLを加えて室温にて１時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加えて塩基性とした。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア株式会社、Chromatorex-NH、溶離液；クロロホルム：メタノール＝１０：１］で精製して、無色固体状の３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｂ）ピリジン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン134mgを得た。
1H NMR (CHLOROFORM-d)δ 1.80 (2 H, ddd, J=13.0, 9.1, 3.7 Hz), 1.91 - 1.98 (2 H, m), 2.84 - 2.91 (2 H, m), 3.03 - 3.14 (2 H, m), 3.90 - 3.97 (2 H, m), 4.17 - 4.26 (2 H, m), 4.37 - 4.46 (2 H, m), 7.20 - 7.28 (1 H, m), 7.77 (1 H, d, J=8.7 Hz) tert-Butyl = 3- (2,3-dihydro- (1,4) dioxino (2,3-b) pyridin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5 ) 153 mg of decane-8-carboxylate was dissolved in 2 mL of chloroform, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to make it basic. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [silica gel; Fuji Silysia Ltd., Chromatorex-NH, eluent; chloroform: methanol = 10: 1] To give 3- (2,3-dihydro- (1,4) dioxino (2,3-b) pyridin-6-yl) -1-oxa-3,8-diazaspiro (4. 5) 134 mg of decan-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.80 (2 H, ddd, J = 13.0, 9.1, 3.7 Hz), 1.91-1.98 (2 H, m), 2.84-2.91 (2 H, m), 3.03-3.14 (2 H, m), 3.90-3.97 (2 H, m), 4.17-4.26 (2 H, m), 4.37-4.46 (2 H, m), 7.20-7.28 (1 H, m), 7.77 (1 H, d, J = 8.7 Hz)
参考例５９
Figure JPOXMLDOC01-appb-I000073
Reference Example 59
Figure JPOXMLDOC01-appb-I000073
２－ブロモ－５Ｈ－ピリド（３，２－ｄ）ピリミジン－６－オン200mg及び炭酸水素ナトリウム297mgをエタノール60mLとテトラヒドロフラン60mLの混合溶媒に懸濁し、１０％パラジウム炭素20mgを加えて水素雰囲気下６９時間撹拌した。不溶物を濾過して除き、濾液を減圧濃縮して、淡褐色固体状の５Ｈ－ピリド（３，２－ｄ）ピリミジン－６－オン（粗精製物）220mgを得た。これを用いて、参考例５４と同様の操作により、淡灰色固体状のｔｅｒｔ－ブチル＝２－（６－オキソ－６Ｈ－ピリド（３，２－ｄ）ピリミジン－５－イル）アセタート89mgを得た。
1H NMR (CHLOROFORM-d)δ 1.49 (9 H, s), 4.98 (2 H, s), 7.15 (1 H, d, J=10.1 Hz), 7.90 (1 H, d, J=10.1 Hz), 8.67 (1 H, s), 9.10 (1 H, s) 2-Bromo-5H-pyrido (3,2-d) pyrimidin-6-one (200 mg) and sodium hydrogen carbonate (297 mg) are suspended in a mixed solvent of 60 mL of ethanol and 60 mL of tetrahydrofuran, and 20 mg of 10% palladium on carbon is added under a hydrogen atmosphere. Stir for hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 220 mg of 5H-pyrido (3,2-d) pyrimidin-6-one (crude purified product) as a light brown solid. Using this, the same operation as in Reference Example 54 was carried out to obtain 89 mg of light gray solid tert-butyl = 2- (6-oxo-6H-pyrido (3,2-d) pyrimidin-5-yl) acetate. It was.
1H NMR (CHLOROFORM-d) δ 1.49 (9 H, s), 4.98 (2 H, s), 7.15 (1 H, d, J = 10.1 Hz), 7.90 (1 H, d, J = 10.1 Hz), 8.67 (1 H, s), 9.10 (1 H, s)
参考例６０
Figure JPOXMLDOC01-appb-I000074
Reference Example 60
Figure JPOXMLDOC01-appb-I000074
ｔｅｒｔ－ブチル＝２－（６－オキソ－６Ｈ－ピリド（３，２－ｄ）ピリミジン－５－イル）アセタート79mgを用いて、参考例５５と同様の操作により、淡褐色固体状の２－（６－オキソ－６Ｈ－ピリド（３，２－ｄ）ピリミジン－５－イル）酢酸の塩酸塩51mgを得た。
1H NMR (DMSO-d6)δ 5.07 (2 H, s), 7.18 (1 H, d, J=9.7 Hz), 8.02 (1 H, d, J=9.7 Hz), 9.09 (1 H, s), 9.19 (1 H, s) Using 79 mg of tert-butyl = 2- (6-oxo-6H-pyrido (3,2-d) pyrimidin-5-yl) acetate in the same manner as in Reference Example 55, a pale brown solid 2- ( 51 mg of 6-oxo-6H-pyrido (3,2-d) pyrimidin-5-yl) acetic acid hydrochloride was obtained.
1H NMR (DMSO-d6) δ 5.07 (2 H, s), 7.18 (1 H, d, J = 9.7 Hz), 8.02 (1 H, d, J = 9.7 Hz), 9.09 (1 H, s), 9.19 (1 H, s)
参考例６１
Figure JPOXMLDOC01-appb-I000075
Reference Example 61
Figure JPOXMLDOC01-appb-I000075
ベンジル＝１－オキサ－６－アザスピロ（２．５）オクタン－６－カルボキシラート318mg及び３－フルオロ－４－メチルアニリン162mgを用いて、参考例２９と同様の操作により、淡褐色油状のベンジル＝４－（（（３－フルオロ－４－メチルフェニル）アミノ）メチル）－４－ヒドロキシピペリジン－１－カルボキシラート301mgを得た。
1H NMR (CHLOROFORM-d)δ 1.49 - 1.76 (4 H, m), 2.13 (3 H, s), 3.07 (1 H, br. s), 3.24 (2 H, br. s), 3.80 - 4.03 (2 H, m), 5.06 - 5.17 (2 H, m), 6.31 - 6.38 (2 H, m), 6.86 - 6.99 (1 H, m), 7.28 - 7.40 (5 H, m) Using a procedure similar to that of Reference Example 29 using 318 mg of benzyl = 1-oxa-6-azaspiro (2.5) octane-6-carboxylate and 162 mg of 3-fluoro-4-methylaniline, benzyl = 301 mg of 4-(((3-fluoro-4-methylphenyl) amino) methyl) -4-hydroxypiperidine-1-carboxylate was obtained.
1H NMR (CHLOROFORM-d) δ 1.49-1.76 (4 H, m), 2.13 (3 H, s), 3.07 (1 H, br. S), 3.24 (2 H, br. S), 3.80-4.03 ( 2 H, m), 5.06-5.17 (2 H, m), 6.31-6.38 (2 H, m), 6.86-6.99 (1 H, m), 7.28-7.40 (5 H, m)
参考例６２
Figure JPOXMLDOC01-appb-I000076
Reference Example 62
Figure JPOXMLDOC01-appb-I000076
ベンジル＝４－（（（３－フルオロ－４－メチルフェニル）アミノ）メチル）－４－ヒドロキシピペリジン－１－カルボキシラート287mgを用いて、参考例４９と同様の操作により、淡褐色油状のベンジル＝３－（３－フルオロ－４－メチルフェニル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－カルボキシラート256mgを得た。
1H NMR (CHLOROFORM-d)δ 1.17 - 1.27 (4 H, m), 2.23 (3 H, s), 3.34 - 3.43 (2 H, m), 3.45 - 3.55 (2 H, m), 3.70 (2 H, s), 5.14 (2 H, s), 7.09 - 7.12 (1 H, m), 7.13 - 7.17 (1 H, m), 7.29 - 7.41 (6 H, m) Benzyl 4-(((3-fluoro-4-methylphenyl) amino) methyl) -4-hydroxypiperidine-1-carboxylate 287 mg of light brown oily benzyl = 256 mg of 3- (3-fluoro-4-methylphenyl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decane-8-carboxylate was obtained.
1H NMR (CHLOROFORM-d) δ 1.17-1.27 (4 H, m), 2.23 (3 H, s), 3.34-3.43 (2 H, m), 3.45-3.55 (2 H, m), 3.70 (2 H , s), 5.14 (2 H, s), 7.09-7.12 (1 H, m), 7.13-7.17 (1 H, m), 7.29-7.41 (6 H, m)
参考例６３
Figure JPOXMLDOC01-appb-I000077
Reference Example 63
Figure JPOXMLDOC01-appb-I000077
ベンジル＝３－（３－フルオロ－４－メチルフェニル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－カルボキシラート250mgを用いて、参考例５０と同様の操作により、無色固体状の３－（３－フルオロ－４－メチルフェニル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン67mgを得た。
1H NMR (DMSO-d6)δ 2.01 - 2.14 (4 H, m), 2.19 (3 H, s), 3.08 - 3.15 (2 H, m), 3.17 - 3.24 (2 H, m), 3.93 (2 H, s), 7.22 (1 H, dd, J=8.3, 1.8 Hz), 7.27 - 7.31 (1 H, m), 7.40 - 7.45 (1 H, m), 8.95 (1 H, br. s.) Similar to Reference Example 50 using 250 mg of benzyl = 3- (3-fluoro-4-methylphenyl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decane-8-carboxylate By the operation, 67 mg of colorless solid 3- (3-fluoro-4-methylphenyl) -1-oxa-3,8-diazaspiro (4.5) decan-2-one was obtained.
1H NMR (DMSO-d6) δ 2.01-2.14 (4 H, m), 2.19 (3 H, s), 3.08-3.15 (2 H, m), 3.17-3.24 (2 H, m), 3.93 (2 H , s), 7.22 (1 H, dd, J = 8.3, 1.8 Hz), 7.27-7.31 (1 H, m), 7.40-7.45 (1 H, m), 8.95 (1 H, br.s.)
参考例６４
Figure JPOXMLDOC01-appb-I000078
Reference Example 64
Figure JPOXMLDOC01-appb-I000078
６－ブロモ－２，３－ジヒドロベンゾ（ｂ）（１，４）ジチイン530mg及びｔｅｒｔ－ブチル＝２－オキソ－３，８－ジアザスピロ（４．５）デカン－８－カルボキシラート553mgを用いて、参考例１４と同様の操作により、褐色油状のｔｅｒｔ－ブチル＝３－（２，３－ジヒドロベンゾ（ｂ）（１，４）ジチイン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－カルボキシラート76mgを得た。
1H NMR (CHLOROFORM-d)δ 1.46 (9 H, s), 1.71 - 1.76 (2 H, m), 1.94 - 1.96 (2 H, m), 3.22 - 3.28 (4 H, m), 3.29 - 3.36 (2 H, m), 3.68 (2 H, s), 3.82 - 3.93 (2 H, m), 7.14 (1 H, d, J=8.7 Hz), 7.29 (1 H, dd, J=8.7, 2.5 Hz), 8.01 (1 H, s) With 530 mg of 6-bromo-2,3-dihydrobenzo (b) (1,4) dithiin and 553 mg of tert-butyl-2-oxo-3,8-diazaspiro (4.5) decane-8-carboxylate, In the same manner as in Reference Example 14, tert-butyl 3- (2,3-dihydrobenzo (b) (1,4) dithiin-6-yl) -2-oxo-1-oxa-3, 76 mg of 8-diazaspiro (4.5) decane-8-carboxylate was obtained.
1H NMR (CHLOROFORM-d) δ 1.46 (9 H, s), 1.71-1.76 (2 H, m), 1.94-1.96 (2 H, m), 3.22-3.28 (4 H, m), 3.29-3.36 ( 2 H, m), 3.68 (2 H, s), 3.82-3.93 (2 H, m), 7.14 (1 H, d, J = 8.7 Hz), 7.29 (1 H, dd, J = 8.7, 2.5 Hz ), 8.01 (1 H, s)
参考例６５
Figure JPOXMLDOC01-appb-I000079
Reference Example 65
Figure JPOXMLDOC01-appb-I000079
ｔｅｒｔ－ブチル＝３－（２，３－ジヒドロベンゾ（ｂ）（１，４）ジチイン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－カルボキシラート33mgを用いて、参考例５８と同様の操作により、淡褐色固体状の３－（２，３－ジヒドロベンゾ（ｂ）（１，４）ジチイン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン14mgを得た。
1H NMR (CHLOROFORM-d)δ 1.77 - 1.81 (2 H, m), 1.94 - 2.00 (2 H, m), 2.89 - 2.92 (2 H, m), 3.09 - 3.12 (2 H, m), 3.23 - 3.29 (4 H, m), 3.69 (2 H, s), 7.15 (1 H, s), 7.28 (1 H, d, J=2.5 Hz), 7.32 (1 H, dd, J=8.7, 2.5 Hz) tert-butyl = 3- (2,3-dihydrobenzo (b) (1,4) dithiin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decane-8- The same operation as in Reference Example 58 was carried out using 33 mg of carboxylate, to give a pale brown solid of 3- (2,3-dihydrobenzo (b) (1,4) dithiin-6-yl) -1-oxa-3 , 8-diazaspiro (4.5) decan-2-one 14 mg was obtained.
1H NMR (CHLOROFORM-d) δ 1.77-1.81 (2 H, m), 1.94-2.00 (2 H, m), 2.89-2.92 (2 H, m), 3.09-3.12 (2 H, m), 3.23- 3.29 (4 H, m), 3.69 (2 H, s), 7.15 (1 H, s), 7.28 (1 H, d, J = 2.5 Hz), 7.32 (1 H, dd, J = 8.7, 2.5 Hz )
参考例６６
Figure JPOXMLDOC01-appb-I000080
Reference Example 66
Figure JPOXMLDOC01-appb-I000080
２－ヨードチエノ（３，２－ｂ）チオフェン463mg及びｔｅｒｔ－ブチル＝２－オキソ－３，８－ジアザスピロ（４．５）デカン－８－カルボキシラート228mgを用いて、参考例１４と同様の操作により、淡褐色固体状のｔｅｒｔ－ブチル＝２－オキソ－３－（チエノ（３，２－ｂ）チオフェン－２－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－カルボキシラート215mgを得た。
1H NMR (CHLOROFORM-d)δ 1.47 (9 H, s), 1.76 - 1.83 (2 H, m), 1.99 - 2.02 (2 H, m), 3.31 - 3.34 (2 H, m), 3.77 (2 H, s), 3.86 - 3.95 (2 H, m), 6.70 (1 H, s), 7.18 (1 H, d, J=5.0 Hz), 7.23 - 7.26 (1 H, m) The same operation as in Reference Example 14 was performed using 463 mg of 2-iodothieno (3,2-b) thiophene and 228 mg of tert-butyl-2-oxo-3,8-diazaspiro (4.5) decane-8-carboxylate. Tert-Butyl-2-oxo-3- (thieno (3,2-b) thiophen-2-yl) -1-oxa-3,8-diazaspiro (4.5) decane-8- 215 mg of carboxylate was obtained.
1H NMR (CHLOROFORM-d) δ 1.47 (9 H, s), 1.76-1.83 (2 H, m), 1.99-2.02 (2 H, m), 3.31-3.34 (2 H, m), 3.77 (2 H , s), 3.86-3.95 (2 H, m), 6.70 (1 H, s), 7.18 (1 H, d, J = 5.0 Hz), 7.23-7.26 (1 H, m)
参考例６７
Figure JPOXMLDOC01-appb-I000081
Reference Example 67
Figure JPOXMLDOC01-appb-I000081
ｔｅｒｔ－ブチル＝２－オキソ－３－（チエノ（３，２－ｂ）チオフェン－２－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－カルボキシラート210mgを用いて、参考例５８と同様の操作により、褐色油状の３－（チエノ（３，２－ｂ）チオフェン－２－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン131mgを得た。
1H NMR (CHLOROFORM-d)δ 1.74 - 1.81 (2 H, m), 1.95 - 1.98 (2 H, m), 2.84 - 2.89 (2 H, m), 3.03 - 3.10 (2 H, m), 3.73 (2 H, s), 6.65 (1 H, s), 7.14 (1 H, d, J=5.4 Hz), 7.19 - 7.21 (1H, m) Using 210 mg of tert-butyl = 2-oxo-3- (thieno (3,2-b) thiophen-2-yl) -1-oxa-3,8-diazaspiro (4.5) decane-8-carboxylate The brown oily 3- (thieno (3,2-b) thiophen-2-yl) -1-oxa-3,8-diazaspiro (4.5) decan-2-one was prepared in the same manner as in Reference Example 58. 131 mg was obtained.
1H NMR (CHLOROFORM-d) δ 1.74-1.81 (2 H, m), 1.95-1.98 (2 H, m), 2.84-2.89 (2 H, m), 3.03-3.10 (2 H, m), 3.73 ( 2 H, s), 6.65 (1 H, s), 7.14 (1 H, d, J = 5.4 Hz), 7.19-7.21 (1H, m)
参考例６８
Figure JPOXMLDOC01-appb-I000082
Reference Example 68
Figure JPOXMLDOC01-appb-I000082
ｔｅｒｔ－ブチル＝６－アミノ－２－アザスピロ（３．３）ヘプタン－２－カルボキシラート119mg及び２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－カルバルデヒド89mgをクロロホルム5mLに溶解し、酢酸46μLを加えて室温にて３時間撹拌した。トリアセトキシ水素化ホウ素ナトリウム250mgを加えて、室温にて２時間撹拌した。反応混合物に水2mLを加え、溶媒を減圧留去した後、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；クロロホルム］で精製して淡黄色油状のｔｅｒｔ－ブチル＝６－（（（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）メチル）アミノ）－２－アザスピロ（３．３）ヘプタン－２－カルボキシラート150mgを得た。
1H NMR (CHLOROFORM-d)δ 1.41 (9 H, br. s.), 1.86 - 1.91 (2 H, m), 2.39 - 2.42 (2 H, m), 3.17 - 3.22 (1 H, m), 3.66 (2 H, s), 3.82 (2 H, s), 3.89 (2 H, s), 4.25 - 4.28 (2 H, m), 4.30 - 4.33 (2 H, m), 6.78 (1 H, s), 8.09 (1 H, s) tert-Butyl = 6-Amino-2-azaspiro (3.3) heptane-2-carboxylate 119 mg and 2,3-dihydro- (1,4) dioxyno (2,3-c) pyridine-7-carbaldehyde 89 mg Was dissolved in chloroform (5 mL), acetic acid (46 μL) was added, and the mixture was stirred at room temperature for 3 hr. 250 mg of sodium triacetoxyborohydride was added and stirred at room temperature for 2 hours. After adding 2 mL of water to the reaction mixture and distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: chloroform] to give a pale yellow oily substance. tert-butyl = 6-(((2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-yl) methyl) amino) -2-azaspiro (3.3) heptane-2 -150 mg of carboxylate were obtained.
1H NMR (CHLOROFORM-d) δ 1.41 (9 H, br.s.), 1.86-1.91 (2 H, m), 2.39-2.42 (2 H, m), 3.17-3.22 (1 H, m), 3.66 (2 H, s), 3.82 (2 H, s), 3.89 (2 H, s), 4.25-4.28 (2 H, m), 4.30-4.33 (2 H, m), 6.78 (1 H, s) , 8.09 (1 H, s)
参考例６９
Figure JPOXMLDOC01-appb-I000083
Reference Example 69
Figure JPOXMLDOC01-appb-I000083
ｔｅｒｔ－ブチル＝６－（（（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）メチル）アミノ）－２－アザスピロ（３．３）ヘプタン－２－カルボキシラート130mgを用いて、参考例５８と同様の操作により、淡黄色油状のＮ－（（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）メチル）－２－アザスピロ（３．３）ヘプタン－６－アミン88mgを得た。
1H NMR (CHLOROFORM-d)δ 1.80 - 1.85 (2 H, m), 2.42 - 2.45 (2 H, m), 3.15 - 3.17 (1 H, m), 3.52 (2 H, s), 3.61 (2 H, s), 3.66 (2 H, s), 4.25 - 4.28 (2 H, m), 4.29 - 4.33 (2 H, m), 6.79 (1 H, s), 8.09 (1 H, s) tert-butyl = 6-(((2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-yl) methyl) amino) -2-azaspiro (3.3) heptane-2 -Using a carboxylate of 130 mg and following the same procedure as in Reference Example 58, a pale yellow oily N-((2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-yl) 88 mg of methyl) -2-azaspiro (3.3) heptane-6-amine were obtained.
1H NMR (CHLOROFORM-d) δ 1.80-1.85 (2 H, m), 2.42-2.45 (2 H, m), 3.15-3.17 (1 H, m), 3.52 (2 H, s), 3.61 (2 H , s), 3.66 (2 H, s), 4.25-4.28 (2 H, m), 4.29-4.33 (2 H, m), 6.79 (1 H, s), 8.09 (1 H, s)
参考例７０
Figure JPOXMLDOC01-appb-I000084
Reference Example 70
Figure JPOXMLDOC01-appb-I000084
（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒドの塩酸塩122mg及びｔｅｒｔ－ブチル＝２，７－ジアザスピロ（４．４）ノナン－２－カルボキシラート123mgを用いて、参考例３５と同様の操作により、褐色泡状のｔｅｒｔ－ブチル＝７－（２－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）エチル）－２，７－ジアザスピロ（４．４）ノナン－２－カルボキシラート126mgを得た。
1H NMR (CHLOROFORM-d)δ 1.45 (9 H, s), 1.72 - 1.90 (4 H, m), 2.68 - 2.82 (4 H, m), 3.15 - 3.29 (2 H, m), 3.28 - 3.45 (4 H, m), 3.97 (3 H, s), 4.35 (2 H, t, J=7.4 Hz), 6.74 (1 H, d, J=9.5 Hz), 7.15 - 7.16 (1 H, m), 7.83 (1 H, d, J=9.5 Hz), 8.27 (1 H, d, J=1.7 Hz) 122 mg of hydrochloride salt of (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde and 123 mg of tert-butyl = 2,7-diazaspiro (4.4) nonane-2-carboxylate In the same manner as in Reference Example 35, brown foamy tert-butyl = 7- (2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl)- 126 mg of 2,7-diazaspiro (4.4) nonane-2-carboxylate was obtained.
1H NMR (CHLOROFORM-d) δ 1.45 (9 H, s), 1.72-1.90 (4 H, m), 2.68-2.82 (4 H, m), 3.15-3.29 (2 H, m), 3.28-3.45 ( 4 H, m), 3.97 (3 H, s), 4.35 (2 H, t, J = 7.4 Hz), 6.74 (1 H, d, J = 9.5 Hz), 7.15-7.16 (1 H, m), 7.83 (1 H, d, J = 9.5 Hz), 8.27 (1 H, d, J = 1.7 Hz)
参考例７１
Figure JPOXMLDOC01-appb-I000085
Reference Example 71
Figure JPOXMLDOC01-appb-I000085
　ｔｅｒｔ－ブチル＝７－（２－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）エチル）－２，７－ジアザスピロ（４．４）ノナン－２－カルボキシラート105mgを用いて、参考例１３の操作と同様にして、褐色固体状の１－（２－（２，７－ジアザスピロ（４．４）ノナ－２－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オンの塩酸塩125mgを得た。
1H NMR (DMSO-d6)δ 1.84 - 2.17 (4 H, m), 3.16 - 3.27 (4 H, m), 3.37 - 3.43 (2 H, m), 3.67 - 3.74 (2 H, m), 3.77 - 3.83 (2 H, m), 4.02 (3 H, s), 4.43 - 4.67 (2 H, m), 6.68 (1 H, d, J=9.5 Hz), 7.62 - 7.69 (1 H, m), 7.89 (1 H, d, J=9.5 Hz), 8.29 (1 H, d, J=2.1 Hz) tert-Butyl = 7- (2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -2,7-diazaspiro (4.4) nonane-2-carboxylate Using 105 mg, in the same manner as in Reference Example 13, 1- (2- (2,7-diazaspiro (4.4) non-2-yl) ethyl) -7-methoxy-1H— in the form of a brown solid 125 mg of (1,5) naphthyridin-2-one hydrochloride was obtained.
1H NMR (DMSO-d6) δ 1.84-2.17 (4 H, m), 3.16-3.27 (4 H, m), 3.37-3.43 (2 H, m), 3.67-3.74 (2 H, m), 3.77- 3.83 (2 H, m), 4.02 (3 H, s), 4.43-4.67 (2 H, m), 6.68 (1 H, d, J = 9.5 Hz), 7.62-7.69 (1 H, m), 7.89 (1 H, d, J = 9.5 Hz), 8.29 (1 H, d, J = 2.1 Hz)
実施例１、２
Figure JPOXMLDOC01-appb-I000086
Examples 1 and 2
Figure JPOXMLDOC01-appb-I000086
１－（２－クロロエチル）－７－フルオロ－１Ｈ－（１，５）－ナフチリジン－２－オン78mgをアセトニトリル1mLに溶解し、３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン91mg及びトリエチルアミン0.05mLを加えて、５０℃で１５時間撹拌した。室温まで冷却後、反応混合物を減圧下で溶媒留去し、シリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；クロロホルム：メタノール＝１０：１］で精製し、１－（２－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－イル）エチル）－７－フルオロ－１Ｈ－（１，５）－ナフチリジン－２－オン（実施例１）14mg及び１－（２－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－オキシド－８－イル）エチル）－７－フルオロ－１Ｈ－（１，５）－ナフチリジン－２－オン（実施例２）3.9mgを得た。
実施例１
1H NMR (CHLOROFORM-d)δ 1.80 - 1.86 (2 H, m), 2.00 - 2.05 (2 H, m), 2.70 - 2.76 (6 H, m), 3.68 (2 H, s), 4.23 - 4.27 (4 H, m), 4.34 (2 H, t, J=7.1 Hz), 6.85 (1 H, d, J=8.7 Hz), 6.87 (1 H, d, J=9.6 Hz), 6.99 (1 H, dd, J=8.7, 2.3 Hz), 7.07 (1 H, d, J=2.3 Hz), 7.47 (1 H, dd, J=10.1, 2.3 Hz), 7.88 - 7.91 (1 H, m), 8.43 (1 H, d, J=2.3 Hz)
実施例２
1H NMR (METHANOL-d3)δ 2.11 (2 H, d, J=13.8 Hz), 2.66 (2 H, td, J=13.9, 4.4 Hz), 3.26 - 3.37 (2 H, m), 3.44 - 3.49 (2 H, m), 3.68 (2 H, dd, J=8.5, 6.6 Hz), 3.72 - 3.80 (2 H, m), 3.92 (2 H, s), 4.20 - 4.26 (4 H, m), 6.84 (1 H, d, J=8.7 Hz), 6.90 (1 H, d, J=9.6 Hz), 6.97 (1 H, dd, J=8.7, 2.8 Hz), 7.14 (1 H, d, J=2.8 Hz), 8.02 (1 H, d, J=9.6 Hz), 8.25 (1 H, dd, J=10.5, 2.3 Hz), 8.52 (1 H, d, J=2.3 Hz) 78 mg of 1- (2-chloroethyl) -7-fluoro-1H- (1,5) -naphthyridin-2-one was dissolved in 1 mL of acetonitrile, and 3- (2,3-dihydrobenzo (1,4) dioxin-6 -Yl) -1-oxa-3,8-diazaspiro (4.5) decan-2-one (91 mg) and triethylamine (0.05 mL) were added, and the mixture was stirred at 50 ° C. for 15 hr. After cooling to room temperature, the reaction mixture was evaporated under reduced pressure, and purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent; chloroform: methanol = 10: 1] to give 1- (2 -(3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-yl) ethyl)- 7-Fluoro-1H- (1,5) -naphthyridin-2-one (Example 1) 14 mg and 1- (2- (3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -2-Oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-oxide-8-yl) ethyl) -7-fluoro-1H- (1,5) -naphthyridin-2-one ( Example 2) 3.9 mg was obtained.
Example 1
1H NMR (CHLOROFORM-d) δ 1.80-1.86 (2 H, m), 2.00-2.05 (2 H, m), 2.70-2.76 (6 H, m), 3.68 (2 H, s), 4.23-4.27 ( 4 H, m), 4.34 (2 H, t, J = 7.1 Hz), 6.85 (1 H, d, J = 8.7 Hz), 6.87 (1 H, d, J = 9.6 Hz), 6.99 (1 H, dd, J = 8.7, 2.3 Hz), 7.07 (1 H, d, J = 2.3 Hz), 7.47 (1 H, dd, J = 10.1, 2.3 Hz), 7.88-7.91 (1 H, m), 8.43 ( (1 H, d, J = 2.3 Hz)
Example 2
1H NMR (METHANOL-d3) δ 2.11 (2 H, d, J = 13.8 Hz), 2.66 (2 H, td, J = 13.9, 4.4 Hz), 3.26-3.37 (2 H, m), 3.44-3.49 ( 2 H, m), 3.68 (2 H, dd, J = 8.5, 6.6 Hz), 3.72-3.80 (2 H, m), 3.92 (2 H, s), 4.20-4.26 (4 H, m), 6.84 (1 H, d, J = 8.7 Hz), 6.90 (1 H, d, J = 9.6 Hz), 6.97 (1 H, dd, J = 8.7, 2.8 Hz), 7.14 (1 H, d, J = 2.8 Hz), 8.02 (1 H, d, J = 9.6 Hz), 8.25 (1 H, dd, J = 10.5, 2.3 Hz), 8.52 (1 H, d, J = 2.3 Hz)
実施例３
Figure JPOXMLDOC01-appb-I000087
Example 3
Figure JPOXMLDOC01-appb-I000087
（７－フルオロ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）酢酸の塩酸塩83mgをＮ，Ｎ－ジメチルホルムアミド3mLに溶解し、３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン78mg、ヘキサフルオロリン酸＝（ベンゾトリアゾール－１－イルオキシ）トリピロリジノホスホニウム210mg、及びジイソプロピルエチルアミン69mgを加え、室温にて２７時間撹拌した。反応混合物に酢酸エチル15mL、飽和炭酸水素ナトリウム水溶液15mL及び水15mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア株式会社、Chromatorex-NH、溶離液；クロロホルム：メタノール＝９８：２］で精製した。さらに精製物にヘキサン15mL及びクロロホルム1mLを加え、析出物を濾取して白色固体状の１－（２－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－イル）－２－オキソエチル）－７－フルオロ－１Ｈ－（１，５）－ナフチリジン－２－オン111mgを得た。
1H NMR (CHLOROFORM-d)δ 1.78 - 1.85 (1 H, m), 1.98 - 2.10 (2 H, m), 2.19 (1 H, dd, J=14.2, 2.3 Hz), 3.20 - 3.26 (1 H, m), 3.74 (3 H, d, J=7.3 Hz), 3.98 - 4.03 (1 H, m), 4.23 - 4.29 (4 H, m), 4.44 - 4.50 (1 H, m), 4.72 (1 H, d, J=16.5 Hz), 5.42 (1 H, d, J=16.5 Hz), 6.87 (1 H, d, J=8.7 Hz), 6.89 (1 H, d, J=9.6 Hz), 6.98 (1 H, dd, J=8.7, 2.8 Hz), 7.08 (1 H, d, J=2.8 Hz), 7.26 - 7.29 (1 H, m), 7.94 - 7.98 (1 H, m), 8.44 (1 H, d, J=2.3 Hz) 83 mg of (7-fluoro-2-oxo-2H- (1,5) -naphthyridin-1-yl) acetic acid hydrochloride was dissolved in 3 mL of N, N-dimethylformamide, and 3- (2,3-dihydrobenzo ( 1,4) Dioxin-6-yl) -1-oxa-3,8-diazaspiro (4.5) decan-2-one 78 mg, hexafluorophosphoric acid = (benzotriazol-1-yloxy) tripyrrolidinophosphonium 210 mg And 69 mg of diisopropylethylamine were added, and the mixture was stirred at room temperature for 27 hours. To the reaction mixture, 15 mL of ethyl acetate, 15 mL of saturated aqueous sodium hydrogen carbonate solution and 15 mL of water were added, and the organic layer was separated. The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Ltd., Chromatorex-NH, eluent: chloroform: methanol = 98: 2]. Further, 15 mL of hexane and 1 mL of chloroform were added to the purified product, and the precipitate was collected by filtration to give 1- (2- (3- (2,3-dihydrobenzo (1,4) dioxin-6-yl)- 111 mg of 2-oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-yl) -2-oxoethyl) -7-fluoro-1H- (1,5) -naphthyridin-2-one was obtained. It was.
1H NMR (CHLOROFORM-d) δ 1.78-1.85 (1 H, m), 1.98-2.10 (2 H, m), 2.19 (1 H, dd, J = 14.2, 2.3 Hz), 3.20-3.26 (1 H, m), 3.74 (3 H, d, J = 7.3 Hz), 3.98-4.03 (1 H, m), 4.23-4.29 (4 H, m), 4.44-4.50 (1 H, m), 4.72 (1 H , d, J = 16.5 Hz), 5.42 (1 H, d, J = 16.5 Hz), 6.87 (1 H, d, J = 8.7 Hz), 6.89 (1 H, d, J = 9.6 Hz), 6.98 ( 1 H, dd, J = 8.7, 2.8 Hz), 7.08 (1 H, d, J = 2.8 Hz), 7.26-7.29 (1 H, m), 7.94-7.98 (1 H, m), 8.44 (1 H , d, J = 2.3 Hz)
実施例４
Figure JPOXMLDOC01-appb-I000088
Example 4
Figure JPOXMLDOC01-appb-I000088
（７－メトキシ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）酢酸の塩酸塩112mgをＮ，Ｎ－ジメチルホルムアミド4mLに溶解し、３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン101mg、ヘキサフルオロリン酸＝（ベンゾトリアゾール－１－イルオキシ）トリピロリジノホスホニウム269mg、及びジイソプロピルエチルアミン0.12mLを加え、室温にて１５時間撹拌した。反応混合物に酢酸エチル20mL及び飽和炭酸水素ナトリウム水溶液10mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液20mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア株式会社、Chromatorex-NH、溶離液；酢酸エチル：メタノール＝９９：１］で精製した。さらに精製物にクロロホルム10mL及びヘキサン150mLを加え、析出物を濾取して白色固体状の１－（２－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－イル）－２－オキソエチル）－７－メトキシ－１Ｈ－（１，５）－ナフチリジン－２－オン119mgを得た。
1H NMR (CHLOROFORM-d)δ 1.75 - 1.81 (1 H, m), 1.94 - 2.00 (1 H, m), 2.02 - 2.06 (1 H, m), 2.12 - 2.16 (1 H, m), 3.18 - 3.25 (1 H, m), 3.67 - 3.74 (3 H, m), 3.96 (3 H, s), 4.03 - 4.08 (1 H, m), 4.23 - 4.28 (4 H, m), 4.44 - 4.48 (1 H, m), 4.73 (1 H, d, J=16.0 Hz), 5.46 (1 H, d, J=16.0 Hz), 6.76 (1 H, d, J=9.6 Hz), 6.87 (1 H, d, J=8.7 Hz), 6.97 (1 H, dd, J=8.7, 2.5 Hz), 7.07 (1 H, d, J=2.5 Hz), 7.08 (1 H, d, J=2.3 Hz), 7.92 (1 H, d, J=9.6 Hz), 8.30 (1 H, d, J=2.3 Hz) 112 mg of (7-methoxy-2-oxo-2H- (1,5) -naphthyridin-1-yl) acetic acid hydrochloride was dissolved in 4 mL of N, N-dimethylformamide, and 3- (2,3-dihydrobenzo ( 1,4) dioxin-6-yl) -1-oxa-3,8-diazaspiro (4.5) decan-2-one 101 mg, hexafluorophosphoric acid = (benzotriazol-1-yloxy) tripyrrolidinophosphonium 269 mg And 0.12 mL of diisopropylethylamine were added, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture, 20 mL of ethyl acetate and 10 mL of a saturated aqueous sodium hydrogen carbonate solution were added, and the organic layer was separated. The organic layer was washed with 20 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Ltd., Chromatorex-NH, eluent: ethyl acetate: methanol = 99: 1]. Further, 10 mL of chloroform and 150 mL of hexane were added to the purified product, and the precipitate was collected by filtration to give 1- (2- (3- (2,3-dihydrobenzo (1,4) dioxin-6-yl)- 119 mg of 2-oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-yl) -2-oxoethyl) -7-methoxy-1H- (1,5) -naphthyridin-2-one It was.
1H NMR (CHLOROFORM-d) δ 1.75-1.81 (1 H, m), 1.94-2.00 (1 H, m), 2.02-2.06 (1 H, m), 2.12-2.16 (1 H, m), 3.18- 3.25 (1 H, m), 3.67-3.74 (3 H, m), 3.96 (3 H, s), 4.03-4.08 (1 H, m), 4.23-4.28 (4 H, m), 4.44-4.48 ( 1 H, m), 4.73 (1 H, d, J = 16.0 Hz), 5.46 (1 H, d, J = 16.0 Hz), 6.76 (1 H, d, J = 9.6 Hz), 6.87 (1 H, d, J = 8.7 Hz), 6.97 (1 H, dd, J = 8.7, 2.5 Hz), 7.07 (1 H, d, J = 2.5 Hz), 7.08 (1 H, d, J = 2.3 Hz), 7.92 (1 H, d, J = 9.6 Hz), 8.30 (1 H, d, J = 2.3 Hz)
実施例５
Figure JPOXMLDOC01-appb-I000089
Example 5
Figure JPOXMLDOC01-appb-I000089
第１工程
（７－メトキシ－２－オキソ－２Ｈ－キノリン－１－イル）酢酸エチル295mgをエタノール5mL－テトラヒドロフラン5mLに溶解し、水酸化ナトリウム187mgの水溶液（5mL）を加え、７０℃にて１．５時間撹拌した。室温まで冷却後、1 mol/L塩酸で酸性とし、析出物を濾取して乾燥し、淡黄色固体状の残留物147mgを得た。
第２工程
第１工程で得た残留物140mg及び３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン173mgをクロロホルム10mLに懸濁し、トリエチルアミン0.42mL、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩204mg及び１－ヒドロキシベンゾトリアゾール１水和物35mgを加え、室温にて３日間撹拌した。反応液にクロロホルム100mL及び水20mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；クロロホルム：メタノール＝１００：１］で精製し、淡褐色泡状の１－（２－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－イル）－２－オキソエチル）－７－メトキシ－１Ｈ－キノリン－２－オン236mgを得た。
1H NMR (CHLOROFORM-d)δ 1.78 (1 H, ddd, J=13.5, 12.4, 4.4 Hz), 1.90 - 1.96 (1 H, m), 2.02 (1 H, dd, J=14.0, 2.1 Hz), 2.11 (1 H, dd, J=13.8, 1.8 Hz), 3.19 - 3.26 (1 H, m), 3.64 - 3.73 (3 H, m), 3.89 (3 H, s), 3.97 - 4.02 (1 H, m), 4.23 - 4.28 (4 H, m), 4.41 - 4.47 (1 H, m), 4.84 (1 H, d, J=16.0 Hz), 5.42 (1 H, d, J=16.0 Hz), 6.55 (1 H, d, J=9.2 Hz), 6.75 (1 H, d, J=1.8 Hz), 6.83 (1 H, dd, J=8.3,1.8 Hz), 6.86 (1 H, d, J=9.2 Hz), 6.95 - 6.98 (1 H, m), 7.07 (1 H, d, J=2.8 Hz), 7.49 (1 H, d, J=8.3 Hz), 7.66 (1 H, d, J=9.2 Hz) First Step (7-Methoxy-2-oxo-2H-quinolin-1-yl) Ethyl acetate (295 mg) is dissolved in ethanol (5 mL) -tetrahydrofuran (5 mL), and an aqueous solution (5 mL) of sodium hydroxide (187 mg) is added. Stir for 5 hours. After cooling to room temperature, the solution was acidified with 1 mol / L hydrochloric acid, and the precipitate was collected by filtration and dried to obtain 147 mg of a pale yellow solid residue.
Second Step 140 mg of the residue obtained in the first step and 3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxa-3,8-diazaspiro (4.5) decane- 173 mg of 2-one was suspended in 10 mL of chloroform, 0.42 mL of triethylamine, 204 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 35 mg of 1-hydroxybenzotriazole monohydrate were added, Stir for days. Chloroform 100mL and water 20mL were added to the reaction liquid, and the organic layer was fractionated. The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: chloroform: methanol = 100: 1] to give 1- (2- (3- ( 2,3-dihydrobenzo (1,4) dioxin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-yl) -2-oxoethyl) -7- 236 mg of methoxy-1H-quinolin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.78 (1 H, ddd, J = 13.5, 12.4, 4.4 Hz), 1.90-1.96 (1 H, m), 2.02 (1 H, dd, J = 14.0, 2.1 Hz), 2.11 (1 H, dd, J = 13.8, 1.8 Hz), 3.19-3.26 (1 H, m), 3.64-3.73 (3 H, m), 3.89 (3 H, s), 3.97-4.02 (1 H, m), 4.23-4.28 (4 H, m), 4.41-4.47 (1 H, m), 4.84 (1 H, d, J = 16.0 Hz), 5.42 (1 H, d, J = 16.0 Hz), 6.55 (1 H, d, J = 9.2 Hz), 6.75 (1 H, d, J = 1.8 Hz), 6.83 (1 H, dd, J = 8.3,1.8 Hz), 6.86 (1 H, d, J = 9.2 Hz), 6.95-6.98 (1 H, m), 7.07 (1 H, d, J = 2.8 Hz), 7.49 (1 H, d, J = 8.3 Hz), 7.66 (1 H, d, J = 9.2 Hz )
実施例６
Figure JPOXMLDOC01-appb-I000090
Example 6
Figure JPOXMLDOC01-appb-I000090
（２－オキソ－２Ｈ－（１，７）－ナフチリジン－１－イル）酢酸エチル105mg及び３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン124mgを用いて実施例５と同様の操作により、淡褐色泡状の１－（２－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－イル）－２－オキソエチル）－１Ｈ－（１，７）－ナフチリジン－２－オン204mgを得た。
1H NMR (CHLOROFORM-d)δ 1.82 (1 H, td, J=13.0, 4.8 Hz), 2.01 (1 H, td, J=13.0, 4.4 Hz), 2.07 (1 H, dd, J=14.0, 2.1 Hz), 2.20 (1 H, dd, J=13.8, 1.8 Hz), 3.21 - 3.27 (1 H, m), 3.71 - 3.79 (3 H, m), 3.95 - 4.01 (1 H, m), 4.24 - 4.28 (4 H, m), 4.45 - 4.50 (1 H, m), 5.07 (1 H, d, J=16.0 Hz), 5.35 (1 H, d, J=16.0 Hz), 6.87 (1 H, d, J=8.7 Hz), 6.92 (1 H, d, J=9.6 Hz), 6.98 (1 H, dd, J=8.7, 2.8 Hz), 7.09 (1 H, d, J=2.8 Hz), 7.44 (1 H, d, J=5.0 Hz), 7.72 (1 H, d, J=9.6 Hz), 8.46 (1 H, d, J=5.0 Hz), 8.61 (1 H, s) 105 mg ethyl (2-oxo-2H- (1,7) -naphthyridin-1-yl) acetate and 3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxa-3, The same operation as in Example 5 was carried out using 124 mg of 8-diazaspiro (4.5) decan-2-one, and 1- (2- (3- (2,3-dihydrobenzo (1,4 ) Dioxin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-yl) -2-oxoethyl) -1H- (1,7) -naphthyridine-2- On 204 mg was obtained.
1H NMR (CHLOROFORM-d) δ 1.82 (1 H, td, J = 13.0, 4.8 Hz), 2.01 (1 H, td, J = 13.0, 4.4 Hz), 2.07 (1 H, dd, J = 14.0, 2.1 Hz), 2.20 (1 H, dd, J = 13.8, 1.8 Hz), 3.21-3.27 (1 H, m), 3.71-3.79 (3 H, m), 3.95-4.01 (1 H, m), 4.24- 4.28 (4 H, m), 4.45-4.50 (1 H, m), 5.07 (1 H, d, J = 16.0 Hz), 5.35 (1 H, d, J = 16.0 Hz), 6.87 (1 H, d , J = 8.7 Hz), 6.92 (1 H, d, J = 9.6 Hz), 6.98 (1 H, dd, J = 8.7, 2.8 Hz), 7.09 (1 H, d, J = 2.8 Hz), 7.44 ( 1 H, d, J = 5.0 Hz), 7.72 (1 H, d, J = 9.6 Hz), 8.46 (1 H, d, J = 5.0 Hz), 8.61 (1 H, s)
実施例７
Figure JPOXMLDOC01-appb-I000091
Example 7
Figure JPOXMLDOC01-appb-I000091
（７－メトキシ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）酢酸の塩酸塩14mg、２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，７－ジアザスピロ（３．５）ノナ－１－オン16mg、ジイソプロピルエチルアミン44.8μL、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩15mg及び１－ヒドロキシベンゾトリアゾール１水和物4mgをＮ，Ｎ－ジメチルホルムアミド2mLに懸濁し、室温にて３．５時間撹拌した。反応混合物に水5mL及び酢酸エチル50mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；クロロホルム：メタノール＝９：１］で精製し、黄色油状の１－（２－（２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，７－ジアザスピロ（３．５）ノナ－７－イル）－２－オキソエチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン15mgを得た。
1H NMR (CHLOROFORM-d)δ 1.82 - 1.91 (1 H, m), 1.96 - 2.09 (2 H, m), 2.12 - 2.19 (1 H, m), 3.38 - 3.45 (2 H, m), 3.73 (1 H, ddd, J=13.1, 9.4, 3.2 Hz), 3.78 - 3.84 (1 H, m), 3.91 - 3.98 (5 H, m), 4.22 - 4.27 (4 H, m), 4.81 (1 H, d, J=16.0 Hz), 5.40 (1 H, d, J=16.0 Hz), 6.78 (1 H, s), 6.83 - 6.86 (2 H, m), 6.89 (1 H, d, J=2.3 Hz), 7.07 (1 H, d, J=2.3 Hz), 7.92 (1 H, d, J=9.6 Hz), 8.29 (1 H, br. s.) (7-Methoxy-2-oxo-2H- (1,5) -naphthyridin-1-yl) acetic acid hydrochloride 14 mg, 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl)- 1-oxo-2,7-diazaspiro (3.5) non-1-one 16 mg, diisopropylethylamine 44.8 μL, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 15 mg and 1-hydroxybenzotriazole 1 4 mg of the hydrate was suspended in 2 mL of N, N-dimethylformamide and stirred at room temperature for 3.5 hours. Water (5 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent; chloroform: methanol = 9: 1] to give 1- (2- (2- (2, 3-Dihydrobenzo (1,4) dioxin-6-yl) -1-oxo-2,7-diazaspiro (3.5) non-7-yl) -2-oxoethyl) -7-methoxy-1H- (1 , 5) 15 mg of naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.82-1.91 (1 H, m), 1.96-2.09 (2 H, m), 2.12-2.19 (1 H, m), 3.38-3.45 (2 H, m), 3.73 ( 1 H, ddd, J = 13.1, 9.4, 3.2 Hz), 3.78-3.84 (1 H, m), 3.91-3.98 (5 H, m), 4.22-4.27 (4 H, m), 4.81 (1 H, d, J = 16.0 Hz), 5.40 (1 H, d, J = 16.0 Hz), 6.78 (1 H, s), 6.83-6.86 (2 H, m), 6.89 (1 H, d, J = 2.3 Hz ), 7.07 (1 H, d, J = 2.3 Hz), 7.92 (1 H, d, J = 9.6 Hz), 8.29 (1 H, br.s.)
実施例８
Figure JPOXMLDOC01-appb-I000092
Example 8
Figure JPOXMLDOC01-appb-I000092
（７－メトキシ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）酢酸の塩酸塩50mg及び２－（（２，３）－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２，６－ジアザスピロ（３．５）－ノナ－１－オン63mgを用いて、実施例７と同様の操作により、無色固体状の１－（２－（２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，６－ジアザスピロ（３．５）ノナ－６－イル）－２－オキソエチル）－７－メトキシ－１Ｈ－（１，５）－ナフチリジン－２－オン32mgを得た。
1H NMR (CHLOROFORM-d)δ 1.31 - 1.62 (1 H, m), 1.79 - 1.98 (2 H, m), 1.99 - 2.18 (1 H, m), 2.68 - 2.79 (1 H, m), 2.82 - 3.02 (1 H, m), 3.11 - 3.21 (1 H, m), 3.25 - 3.37 (1 H, m), 3.52 - 3.74 (2 H, m), 3.96 - 4.06 (3 H, m), 4.19 - 4.29 (4 H, m), 4.40 - 4.56 (1 H, m), 4.60 - 4.77 (1 H, m), 6.67 - 6.86 (4 H, m), 7.39 - 7.47 (1 H, m), 7.82 - 7.92 (1 H, m), 8.26 - 8.32 (1 H, m) 50 mg of (7-methoxy-2-oxo-2H- (1,5) -naphthyridin-1-yl) acetic acid hydrochloride and 2-((2,3) -dihydrobenzo (1,4) dioxin-6-yl ) -2,6-Diazaspiro (3.5) -non-1-one By the same operation as in Example 7, using colorless solid 1- (2- (2- (2,3-dihydro) Benzo (1,4) dioxin-6-yl) -1-oxo-2,6-diazaspiro (3.5) non-6-yl) -2-oxoethyl) -7-methoxy-1H- (1,5) -32 mg of naphthyridin-2-one were obtained.
1H NMR (CHLOROFORM-d) δ 1.31-1.62 (1 H, m), 1.79-1.98 (2 H, m), 1.99-2.18 (1 H, m), 2.68-2.79 (1 H, m), 2.82- 3.02 (1 H, m), 3.11-3.21 (1 H, m), 3.25-3.37 (1 H, m), 3.52-3.74 (2 H, m), 3.96-4.06 (3 H, m), 4.19- 4.29 (4 H, m), 4.40-4.56 (1 H, m), 4.60-4.77 (1 H, m), 6.67-6.86 (4 H, m), 7.39-7.47 (1 H, m), 7.82- 7.92 (1 H, m), 8.26-8.32 (1 H, m)
実施例９
Figure JPOXMLDOC01-appb-I000093
Example 9
Figure JPOXMLDOC01-appb-I000093
（７－メトキシ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）酢酸の塩酸塩42mg及び２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－３－オン43mgをＮ，Ｎ－ジメチルホルムアミド5mLに懸濁し、トリエチルアミン0.09mL、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩31.9mg及び１－ヒドロキシベンゾトリアゾール１水和物25.9mgを加え、室温にて１日、６０℃で３時間撹拌した。反応混合物に水10mL及びクロロホルム50mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を分取用シリカゲル薄層クロマトグラフィー［メルク株式会社製ＰＬＣプレートシリカゲル６０Ｆ２５４、展開液；クロロホルム／メタノール＝４０／１）］で精製し、１－（２－（２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－８－イル）－２－オキソエチル）－７－メトキシ－１Ｈ－（１，５）－ナフチリジン－２－オン60mgを得た。
1H NMR (CHLOROFORM-d)δ 1.64 - 1.75 (2 H, m), 1.75 - 1.86 (2 H, m), 2.55 (2 H, s), 3.34 - 3.45 (1 H, m), 3.54 - 3.60 (1 H, m), 3.61 (2 H, s), 3.75 - 3.83 (1 H, m), 3.85 - 3.92 (1 H, m), 3.96 (3 H, s), 4.21 - 4.29 (4 H, m), 4.98 (1 H, d, J=15.6 Hz), 5.21 (1 H, d, J=16.5 Hz), 6.77 (1 H, d, J=10.1 Hz), 6.86 (1 H, d, J=8.7 Hz), 7.01 (1 H, dd, J=8.7, 2.3 Hz), 7.10 (1 H, d, J=2.3 Hz), 7.12 (1 H, br. s.), 7.91 (1 H, d, J=10.1 Hz), 8.29 (1 H, d, J=2.3 Hz) 42 mg of (7-methoxy-2-oxo-2H- (1,5) -naphthyridin-1-yl) acetic acid hydrochloride and 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl)- 43 mg of 3-oxo-2,8-diazaspiro (4.5) decan-3-one is suspended in 5 mL of N, N-dimethylformamide, 0.09 mL of triethylamine, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide 31.9 mg of hydrochloride and 25.9 mg of 1-hydroxybenzotriazole monohydrate were added, and the mixture was stirred at room temperature for 1 day at 60 ° C. for 3 hours. 10 mL of water and 50 mL of chloroform were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography [PLC plate silica gel 60F 254 , developed by Merck & Co., developing solution: chloroform / methanol = 40/1)], and 1- (2- (2- ( 2,3-dihydrobenzo (1,4) dioxin-6-yl) -3-oxo-2,8-diazaspiro (4.5) decan-8-yl) -2-oxoethyl) -7-methoxy-1H- 60 mg of (1,5) -naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.64-1.75 (2 H, m), 1.75-1.86 (2 H, m), 2.55 (2 H, s), 3.34-3.45 (1 H, m), 3.54-3.60 ( 1 H, m), 3.61 (2 H, s), 3.75-3.83 (1 H, m), 3.85-3.92 (1 H, m), 3.96 (3 H, s), 4.21-4.29 (4 H, m ), 4.98 (1 H, d, J = 15.6 Hz), 5.21 (1 H, d, J = 16.5 Hz), 6.77 (1 H, d, J = 10.1 Hz), 6.86 (1 H, d, J = 8.7 Hz), 7.01 (1 H, dd, J = 8.7, 2.3 Hz), 7.10 (1 H, d, J = 2.3 Hz), 7.12 (1 H, br.s.), 7.91 (1 H, d, J = 10.1 Hz), 8.29 (1 H, d, J = 2.3 Hz)
実施例１０
Figure JPOXMLDOC01-appb-I000094
Example 10
Figure JPOXMLDOC01-appb-I000094
第１工程
３－（７－メトキシ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）プロピオン酸エチル200mgをメタノール3mL－水1mLに溶解し、水酸化リチウム１水和物46mgを加え、室温にて１９時間撹拌した。反応混合物に1 mol/L塩酸を加えて酸性とし、減圧下溶媒留去して、残留物105mgを得た。
第２工程
得られた残留物35mg（残りの70mgは実施例１１で使用）及び２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－３－オン34mgを用いて、実施例５第２工程と同様の操作により、１－（３－（２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－８－イル）－３－オキソプロピル）－７－メトキシ－１Ｈ－（１，５）－ナフチリジン－２－オン21mgを得た。
1H NMR (CHLOROFORM-d)δ 1.58 - 1.66 (2 H, m), 2.47 (2 H, d, J=4.1 Hz), 2.75 - 2.90 (2 H, m), 3.31 - 3.40 (2 H, m), 3.50 - 3.58 (4 H, m), 3.81 - 3.89 (1 H, m), 3.99 (3 H, s), 4.21 - 4.27 (5 H, m), 4.50 - 4.63 (2 H, m), 6.75 (1 H, d, J=10.1 Hz), 6.85 (1 H, d, J=8.7 Hz), 6.99 (1 H, dd, J=8.7, 2.3 Hz), 7.10 (1 H, d, J=2.3 Hz), 7.43 (1 H, d, J=2.3 Hz), 7.88 (1 H, d, J=10.1 Hz), 8.29 (1 H, d, J=2.3 Hz) Step 1 3- (7-Methoxy-2-oxo-2H- (1,5) -naphthyridin-1-yl) ethyl propionate 200 mg is dissolved in methanol 3 mL-water 1 mL, and lithium hydroxide monohydrate 46 mg And stirred at room temperature for 19 hours. The reaction mixture was acidified with 1 mol / L hydrochloric acid and evaporated under reduced pressure to give 105 mg of residue.
Second Step 35 mg of residue obtained (the remaining 70 mg used in Example 11) and 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -3-oxo-2,8- 1- (3- (2- (2,3-dihydrobenzo (1,4) dioxin-) was prepared by the same procedure as in Example 5, Step 2 using 34 mg of diazaspiro (4.5) decan-3-one. 6-yl) -3-oxo-2,8-diazaspiro (4.5) decan-8-yl) -3-oxopropyl) -7-methoxy-1H- (1,5) -naphthyridin-2-one 21 mg Got.
1H NMR (CHLOROFORM-d) δ 1.58-1.66 (2 H, m), 2.47 (2 H, d, J = 4.1 Hz), 2.75-2.90 (2 H, m), 3.31-3.40 (2 H, m) , 3.50-3.58 (4 H, m), 3.81-3.89 (1 H, m), 3.99 (3 H, s), 4.21-4.27 (5 H, m), 4.50-4.63 (2 H, m), 6.75 (1 H, d, J = 10.1 Hz), 6.85 (1 H, d, J = 8.7 Hz), 6.99 (1 H, dd, J = 8.7, 2.3 Hz), 7.10 (1 H, d, J = 2.3 Hz), 7.43 (1 H, d, J = 2.3 Hz), 7.88 (1 H, d, J = 10.1 Hz), 8.29 (1 H, d, J = 2.3 Hz)
実施例１１
Figure JPOXMLDOC01-appb-I000095
Example 11
Figure JPOXMLDOC01-appb-I000095
実施例１０で得た残留物70mg及び３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン68mgを用いて、実施例５の第２工程と同様の操作により、白色固体状の１－（３－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－イル）－３－オキソプロピル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン67mgを得た。
1H NMR (CHLOROFORM-d)δ 1.57 - 1.64 (2 H, m), 2.00 (2 H, d, J=13.8 Hz), 2.76 (1 H, ddd, J=15.0, 8.8, 6.0 Hz), 2.91 (1 H, ddd, J=15.4, 8.5, 6.4 Hz), 3.10 - 3.16 (1 H, m), 3.45 - 3.51 (1 H, m), 3.64 (2 H, d, J=1.4 Hz), 3.77 (1 H, d, J=14.2 Hz), 4.00 (3 H, s), 4.23 - 4.27 (4 H, m), 4.46 (1 H, d, J=13.8 Hz), 4.52 (1 H, ddd, J=14.2, 8.5, 5.7 Hz), 4.59 - 4.65 (1 H, m), 6.75 (1 H, d, J=9.6 Hz), 6.85 (1 H, d, J=8.7 Hz), 6.93 - 6.96 (1 H, m), 7.05 (1 H, d, J=2.3 Hz), 7.41 (1 H, d, J=2.3 Hz), 7.88 (1 H, d, J=9.6 Hz), 8.29 (1 H, d, J=2.3 Hz) 70 mg of the residue obtained in Example 10 and 3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxa-3,8-diazaspiro (4.5) decan-2-one Using 1 mg of white solid 1- (3- (3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -2 in the same manner as in the second step of Example 5, using 68 mg There was obtained 67 mg of -oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-yl) -3-oxopropyl) -7-methoxy-1H- (1,5) naphthyridin-2-one .
1H NMR (CHLOROFORM-d) δ 1.57-1.64 (2 H, m), 2.00 (2 H, d, J = 13.8 Hz), 2.76 (1 H, ddd, J = 15.0, 8.8, 6.0 Hz), 2.91 ( 1 H, ddd, J = 15.4, 8.5, 6.4 Hz), 3.10-3.16 (1 H, m), 3.45-3.51 (1 H, m), 3.64 (2 H, d, J = 1.4 Hz), 3.77 ( 1 H, d, J = 14.2 Hz), 4.00 (3 H, s), 4.23-4.27 (4 H, m), 4.46 (1 H, d, J = 13.8 Hz), 4.52 (1 H, ddd, J = 14.2, 8.5, 5.7 Hz), 4.59-4.65 (1 H, m), 6.75 (1 H, d, J = 9.6 Hz), 6.85 (1 H, d, J = 8.7 Hz), 6.93-6.96 (1 H, m), 7.05 (1 H, d, J = 2.3 Hz), 7.41 (1 H, d, J = 2.3 Hz), 7.88 (1 H, d, J = 9.6 Hz), 8.29 (1 H, d , J = 2.3 Hz)
実施例１２
Figure JPOXMLDOC01-appb-I000096
Example 12
Figure JPOXMLDOC01-appb-I000096
７－メトキシ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）酢酸の塩酸塩40mg及び２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，９－ジアザスピロ（５．５）ウンデカン－１－オンの塩酸塩50mgをＮ，Ｎ－ジメチルホルムアミド5mLに懸濁し、ジイソプロピルエチルアミン129μLを加えて溶解させた。さらに１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩52mg及び１－ヒドロキシベンゾトリアゾール１水和物11mgを加え、室温にて１６．５時間撹拌した。反応混合物に水10mL及びクロロホルム50mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を分取用シリカゲル薄層クロマトグラフィー［メルク株式会社製ＰＬＣプレートシリカゲル６０Ｆ２５４、展開液；クロロホルム／メタノール＝９／１）］で精製し、黄色油状の１－（２－（２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，９－ジアザスピロ（５．５）ウンデカン－９－イル）－２－オキソエチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン90mgを得た。
1H NMR (CHLOROFORM-d)δ 1.48 - 1.58 (1 H, m), 1.59 - 1.66 (1 H, m), 1.85 - 1.90 (2 H, m), 1.92 - 2.04 (2 H, m), 2.10 - 2.17 (1 H, m), 2.20 - 2.27 (1 H, m), 3.55 - 3.63 (2 H, m), 3.64 - 3.71 (1 H, m), 3.73 - 3.79 (1 H, m), 3.79 - 3.86 (1 H, m), 3.92 (3 H, s), 3.98 - 4.05 (1 H, m), 4.25 (4 H, s), 4.71 (1 H, d, J=16.0 Hz), 5.48 (1 H, d, J=16.0 Hz), 6.66 (1 H, dd, J=8.7, 2.3 Hz), 6.71 (1 H, d, J=2.3 Hz), 6.76 (1 H, d, J=9.6 Hz), 6.88 (1 H, m), 7.00 (1 H, d, J=2.3 Hz), 7.89 (1 H, d, J=9.6 Hz), 8.26 (1 H, d, J=2.3 Hz) 7-methoxy-2-oxo-2H- (1,5) -naphthyridin-1-yl) acetic acid hydrochloride 40 mg and 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1 50 mg of hydrochloride of -oxo-2,9-diazaspiro (5.5) undecan-1-one was suspended in 5 mL of N, N-dimethylformamide, and dissolved by adding 129 μL of diisopropylethylamine. Further, 52 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 11 mg of 1-hydroxybenzotriazole monohydrate were added, and the mixture was stirred at room temperature for 16.5 hours. 10 mL of water and 50 mL of chloroform were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography [PLC plate silica gel 60F 254 , developed by Merck & Co., developing solution: chloroform / methanol = 9/1)] to give 1- (2- (2- ( 2- (2,3-Dihydrobenzo (1,4) dioxin-6-yl) -1-oxo-2,9-diazaspiro (5.5) undecan-9-yl) -2-oxoethyl) -7-methoxy 90 mg of -1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.48-1.58 (1 H, m), 1.59-1.66 (1 H, m), 1.85-1.90 (2 H, m), 1.92-2.04 (2 H, m), 2.10- 2.17 (1 H, m), 2.20-2.27 (1 H, m), 3.55-3.63 (2 H, m), 3.64-3.71 (1 H, m), 3.73-3.79 (1 H, m), 3.79- 3.86 (1 H, m), 3.92 (3 H, s), 3.98-4.05 (1 H, m), 4.25 (4 H, s), 4.71 (1 H, d, J = 16.0 Hz), 5.48 (1 H, d, J = 16.0 Hz), 6.66 (1 H, dd, J = 8.7, 2.3 Hz), 6.71 (1 H, d, J = 2.3 Hz), 6.76 (1 H, d, J = 9.6 Hz) , 6.88 (1 H, m), 7.00 (1 H, d, J = 2.3 Hz), 7.89 (1 H, d, J = 9.6 Hz), 8.26 (1 H, d, J = 2.3 Hz)
実施例１３
Figure JPOXMLDOC01-appb-I000097
Example 13
Figure JPOXMLDOC01-appb-I000097
第１工程
（７－メトキシ－２－オキソ－２Ｈ－キノキサリン－１－イル）酢酸エチル280mgをメタノール9mLに溶解し、２０％水酸化ナトリウム水溶液1mLを加え、室温にて１．５時間撹拌した。反応混合物を3 mol/L塩酸で中和し、減圧下溶媒留去して、残留物461mgを得た。
第２工程
第１工程で得た残留物230mg（残りは実施例１４で使用）及び３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン154mgを用いて、実施例５の第２工程と同様の操作により、無色粉末状の１－（２－（３－（２，３－ジヒドロキシベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－イル）－２－
オキソエチル）－７－メトキシ－１Ｈ－キノキサリン－２－オン91mgを得た。
1H NMR (CHLOROFORM-d)δ 1.76 - 1.83 (1 H, m), 1.95 (1 H, td, J=12.8, 4.6 Hz), 2.04 (1 H, dd, J=14.0, 2.1 Hz), 2.15 (1 H, dd, J=13.8, 2.3 Hz), 3.18 - 3.27 (1 H, m), 3.65 - 3.75 (3 H, m), 3.90 (3 H, s), 3.95 (1 H, d, J=13.8 Hz), 4.22 - 4.28 (4 H, m), 4.44 (1 H, d, J=13.8 Hz), 4.79 (1 H, d, J=16.0 Hz), 5.30 (1 H, d, J=16.0 Hz), 6.64 (1 H, d, J=2.3 Hz), 6.86 (1 H, d, J=8.7 Hz), 6.90 - 6.98 (2 H, m), 7.07 (1 H, d, J=2.8 Hz), 7.80 (1 H, d, J=8.7 Hz), 8.15 (1 H, s) First Step (7-methoxy-2-oxo-2H-quinoxalin-1-yl) 280 mg of ethyl acetate was dissolved in 9 mL of methanol, 1 mL of 20% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was neutralized with 3 mol / L hydrochloric acid, and the solvent was distilled off under reduced pressure to obtain 461 mg of residue.
Second Step 230 mg of the residue obtained in the first step (the rest is used in Example 14) and 3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxa-3,8 Using diazaspiro (4.5) decan-2-one (154 mg) in the same manner as in the second step of Example 5, 1- (2- (3- (2,3-dihydroxybenzo ( 1,4) dioxin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-yl) -2-
91 mg of oxoethyl) -7-methoxy-1H-quinoxalin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.76-1.83 (1 H, m), 1.95 (1 H, td, J = 12.8, 4.6 Hz), 2.04 (1 H, dd, J = 14.0, 2.1 Hz), 2.15 ( 1 H, dd, J = 13.8, 2.3 Hz), 3.18-3.27 (1 H, m), 3.65-3.75 (3 H, m), 3.90 (3 H, s), 3.95 (1 H, d, J = 13.8 Hz), 4.22-4.28 (4 H, m), 4.44 (1 H, d, J = 13.8 Hz), 4.79 (1 H, d, J = 16.0 Hz), 5.30 (1 H, d, J = 16.0 Hz), 6.64 (1 H, d, J = 2.3 Hz), 6.86 (1 H, d, J = 8.7 Hz), 6.90-6.98 (2 H, m), 7.07 (1 H, d, J = 2.8 Hz ), 7.80 (1 H, d, J = 8.7 Hz), 8.15 (1 H, s)
実施例１４
Figure JPOXMLDOC01-appb-I000098
Example 14
Figure JPOXMLDOC01-appb-I000098
実施例１２の第１工程で得た残留物230mg及び２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－３－オン154mgを用いて、実施例５第２工程と同様の操作により、無色粉末状の１－（２－（２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－８－イル）－２－オキソエチル）－７－メトキシ－１Ｈ－キノキサリン－２－オン135mgを得た。
1H NMR (CHLOROFORM-d)δ 1.71 (2 H, td, J=9.4, 4.1 Hz), 1.80 - 1.84 (2 H, m), 2.55 (2 H, s), 3.38 - 3.44 (1 H, m), 3.52 - 3.58 (1 H, m), 3.62 (2 H, s), 3.69 - 3.76 (1 H, m), 3.85 - 3.92 (4 H, m), 4.22 - 4.27 (4 H, m), 4.92 - 4.98 (1 H, m), 5.08 - 5.14 (1 H, m), 6.63 (1 H, d, J=2.5 Hz), 6.85 (1 H, d, J=8.7 Hz), 6.92 (1 H, dd, J=8.7, 2.5 Hz), 7.01 (1 H, dd, J=8.7, 2.3 Hz), 7.13 (1 H, d, J=2.3 Hz), 7.80 (1 H, d, J=8.7 Hz), 8.15 (1 H, s) 230 mg of the residue obtained in the first step of Example 12 and 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -3-oxo-2,8-diazaspiro (4.5) decane Using 1- (2- (2- (2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) in the form of colorless powder by the same procedure as in Step 5 of Example 5 using 154 mg of -3-one. ) -3-oxo-2,8-diazaspiro (4.5) decan-8-yl) -2-oxoethyl) -7-methoxy-1H-quinoxalin-2-one 135 mg was obtained.
1H NMR (CHLOROFORM-d) δ 1.71 (2 H, td, J = 9.4, 4.1 Hz), 1.80-1.84 (2 H, m), 2.55 (2 H, s), 3.38-3.44 (1 H, m) , 3.52-3.58 (1 H, m), 3.62 (2 H, s), 3.69-3.76 (1 H, m), 3.85-3.92 (4 H, m), 4.22-4.27 (4 H, m), 4.92 -4.98 (1 H, m), 5.08-5.14 (1 H, m), 6.63 (1 H, d, J = 2.5 Hz), 6.85 (1 H, d, J = 8.7 Hz), 6.92 (1 H, dd, J = 8.7, 2.5 Hz), 7.01 (1 H, dd, J = 8.7, 2.3 Hz), 7.13 (1 H, d, J = 2.3 Hz), 7.80 (1 H, d, J = 8.7 Hz) , 8.15 (1 H, s)
実施例１５
Figure JPOXMLDOC01-appb-I000099
Example 15
Figure JPOXMLDOC01-appb-I000099
１－（２－（４－（（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イルアミノ）メチル）－４－ヒドロキシシクロヘキシル）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン（参考例２９：ジアステレオマーＡ）21mgをクロロホルム1mLに溶解し、トリエチルアミン0.02mL及び炭酸ビス(トリクロロメチル)14mgを加えて、窒素雰囲気下室温にて５０分撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液2mL及びクロロホルム5mLを加えて、有機層を分取した。有機層を飽和塩化ナトリウム水溶液2mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を分取用シリカゲル薄層クロマトグラフィー［メルク株式会社製ＰＬＣプレートシリカゲル６０Ｆ２５４、展開液；酢酸エチル）］で精製し、白色固体状の１－（２－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３－アザスピロ（４．５）デカン－８－イル）エチル）－７－フルオロ－１Ｈ－（１，５）－ナフチリジン－２－オン（ジアステレオマーＡ）16mgを得た。
1H NMR (CHLOROFORM-d)δ 1.50 - 1.58 (2 H, m), 1.58 - 1.65 (3 H, m), 1.65 - 1.70 (2 H, m), 1.83 - 1.88 (2 H, m), 2.09 - 2.13 (2 H, m), 3.64 (2 H, s), 4.22 - 4.28 (6 H, m), 6.86 (2 H, m), 7.00 (1 H, dd, J=8.7, 2.8 Hz), 7.07 (1 H, d, J=2.8 Hz), 7.32 (1 H, dd, J=10.1, 1.8 Hz), 7.87 - 7.90 (1 H, m), 8.43 (1 H, d, J=1.8 Hz) 1- (2- (4-((2,3-dihydrobenzo (1,4) dioxin-6-ylamino) methyl) -4-hydroxycyclohexyl) ethyl) -7-fluoro-1H- (1,5) naphthyridine 21 mg of -2-one (Reference Example 29: Diastereomer A) was dissolved in 1 mL of chloroform, 0.02 mL of triethylamine and 14 mg of bis (trichloromethyl) carbonate were added, and the mixture was stirred at room temperature for 50 minutes under a nitrogen atmosphere. To the reaction mixture, 2 mL of saturated aqueous sodium hydrogen carbonate solution and 5 mL of chloroform were added, and the organic layer was separated. The organic layer was washed with 2 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography [PLC plate silica gel 60F 254 , developed by Merck Ltd., developing solution: ethyl acetate]] to give 1- (2- (3- (2 , 3-Dihydrobenzo (1,4) dioxin-6-yl) -2-oxo-1-oxa-3-azaspiro (4.5) decan-8-yl) ethyl) -7-fluoro-1H- (1 , 5) -Naphthyridin-2-one (Diastereomer A) 16 mg was obtained.
1H NMR (CHLOROFORM-d) δ 1.50-1.58 (2 H, m), 1.58-1.65 (3 H, m), 1.65-1.70 (2 H, m), 1.83-1.88 (2 H, m), 2.09- 2.13 (2 H, m), 3.64 (2 H, s), 4.22-4.28 (6 H, m), 6.86 (2 H, m), 7.00 (1 H, dd, J = 8.7, 2.8 Hz), 7.07 (1 H, d, J = 2.8 Hz), 7.32 (1 H, dd, J = 10.1, 1.8 Hz), 7.87-7.90 (1 H, m), 8.43 (1 H, d, J = 1.8 Hz)
実施例１６
Figure JPOXMLDOC01-appb-I000100
Example 16
Figure JPOXMLDOC01-appb-I000100
１－（２－（４－（（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イルアミノ）メチル）－４－ヒドロキシシクロヘキシル）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン（参考例２９：ジアステレオマーＢ）18mgを用いて、実施例１５と同様の操作により、無色泡状の１－（２－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３－アザスピロ（４．５）デカン－８－イル）エチル）－７－フルオロ－１Ｈ－（１，５）－ナフチリジン－２－オン（ジアステレオマーＢ）15mgを得た。
1H NMR (CHLOROFORM-d)δ 1.17 - 1.24 (2 H, m), 1.58 - 1.64 (1 H, m), 1.64 - 1.69 (2 H, m), 1.86 (2 H, td, J=12.8, 4.1 Hz), 1.96 - 2.00 (2 H, m), 2.03 - 2.08 (2 H, m), 3.72 (2 H, s), 4.21 - 4.27 (6 H, m), 6.85 (1 H, d, J=8.7 Hz), 6.87 (1 H, d, J=9.6 Hz), 7.01 (1 H, dd, J=8.7, 2.8 Hz), 7.10 (1 H, d, J=2.8 Hz), 7.31 (1 H, dd, J=10.1, 2.3 Hz), 7.89 (1 H, d, J=9.6 Hz), 8.44 (1 H, d, J=2.3 Hz) 1- (2- (4-((2,3-dihydrobenzo (1,4) dioxin-6-ylamino) methyl) -4-hydroxycyclohexyl) ethyl) -7-fluoro-1H- (1,5) naphthyridine By using the same procedure as in Example 15 using 18 mg of -2-one (Reference Example 29: Diastereomer B), colorless foamy 1- (2- (3- (2,3-dihydrobenzo (1, 4) Dioxin-6-yl) -2-oxo-1-oxa-3-azaspiro (4.5) decan-8-yl) ethyl) -7-fluoro-1H- (1,5) -naphthyridine-2- 15 mg of on (diastereomer B) was obtained.
1H NMR (CHLOROFORM-d) δ 1.17-1.24 (2 H, m), 1.58-1.64 (1 H, m), 1.64-1.69 (2 H, m), 1.86 (2 H, td, J = 12.8, 4.1 Hz), 1.96-2.00 (2 H, m), 2.03-2.08 (2 H, m), 3.72 (2 H, s), 4.21-4.27 (6 H, m), 6.85 (1 H, d, J = 8.7 Hz), 6.87 (1 H, d, J = 9.6 Hz), 7.01 (1 H, dd, J = 8.7, 2.8 Hz), 7.10 (1 H, d, J = 2.8 Hz), 7.31 (1 H, dd, J = 10.1, 2.3 Hz), 7.89 (1 H, d, J = 9.6 Hz), 8.44 (1 H, d, J = 2.3 Hz)
実施例１７
Figure JPOXMLDOC01-appb-I000101
Example 17
Figure JPOXMLDOC01-appb-I000101
１－（２－（４－（（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イルアミノ）メチル）－４－ヒドロキシシクロヘキシリデン）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン39mgを用いて、実施例１５と同様の操作により、無色泡状の１－（２－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３－アザスピロ（４．５）デカン－８－イリデン）エチル）－７－フルオロ－１Ｈ－（１，５）－ナフチリジン－２－オン12mgを得た。
1H NMR (CHLOROFORM-d)δ 1.70 (1 H, td, J=12.6, 4.6 Hz), 1.77 - 1.83 (1 H, m), 2.07 - 2.12 (1 H, m), 2.13 - 2.18 (1 H, m), 2.20 - 2.25 (1 H, m), 2.54 - 2.63 (2 H, m), 2.73 - 2.78 (1 H, m), 3.65 - 3.72 (2 H, m), 4.23 - 4.27 (4 H, m), 4.63 - 4.68 (1 H, m), 5.13 (1 H, dd, J=16.0, 6.9 Hz), 5.21 (1 H, t, J=6.4 Hz), 6.86 (1 H, d, J=8.7 Hz), 6.88 (1 H, d, J=9.6 Hz), 7.00 (1 H, dd, J=8.7, 2.8 Hz), 7.08 (1 H, d, J=2.8 Hz), 7.31 (1 H, dd, J=10.1, 2.3 Hz), 7.89 (1 H, d, J=9.6 Hz), 8.43 (1 H, d, J=2.3 Hz) 1- (2- (4-((2,3-dihydrobenzo (1,4) dioxin-6-ylamino) methyl) -4-hydroxycyclohexylidene) ethyl) -7-fluoro-1H- (1,5 ) 1- (2- (3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) in the form of colorless foam by the same operation as in Example 15 using 39 mg of naphthyridin-2-one -12-Oxo-1-oxa-3-azaspiro (4.5) decan-8-ylidene) ethyl) -7-fluoro-1H- (1,5) -naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.70 (1 H, td, J = 12.6, 4.6 Hz), 1.77-1.83 (1 H, m), 2.07-2.12 (1 H, m), 2.13-2.18 (1 H, m), 2.20-2.25 (1 H, m), 2.54-2.63 (2 H, m), 2.73-2.78 (1 H, m), 3.65-3.72 (2 H, m), 4.23-4.27 (4 H, m), 4.63-4.68 (1 H, m), 5.13 (1 H, dd, J = 16.0, 6.9 Hz), 5.21 (1 H, t, J = 6.4 Hz), 6.86 (1 H, d, J = 8.7 Hz), 6.88 (1 H, d, J = 9.6 Hz), 7.00 (1 H, dd, J = 8.7, 2.8 Hz), 7.08 (1 H, d, J = 2.8 Hz), 7.31 (1 H, dd, J = 10.1, 2.3 Hz), 7.89 (1 H, d, J = 9.6 Hz), 8.43 (1 H, d, J = 2.3 Hz)
実施例１８
Figure JPOXMLDOC01-appb-I000102
Example 18
Figure JPOXMLDOC01-appb-I000102
１－（２－（４－（（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イルアミノ）メチル）－４－ヒドロキシシクロヘキシリデン）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン140mgを用いて、実施例１５と同様の操作により、無色泡状の１－（２－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３－アザスピロ（４．５）デカン－８－イリデン）エチル）－７－メトキシ－１Ｈ－（１，５）－ナフチリジン－２－オン107mgを得た。
1H NMR (CHLOROFORM-d)δ 1.67 - 1.74 (1 H, m), 1.77 - 1.84 (1 H, m), 2.07 - 2.12 (1 H, m), 2.16 (1 H, dt, J=13.8, 4.4 Hz), 2.22 (1 H, ddt, J=9.1, 6.8, 4.4, 4.4 Hz), 2.52 - 2.62 (2 H, m), 2.78 (1 H, dt, J=13.8, 4.4 Hz), 3.65 - 3.72 (2 H, m), 3.97 (3 H, s), 4.22 - 4.27 (4 H, m), 4.57 (1 H, dd, J=14.9, 5.7 Hz), 5.21 - 5.30 (2 H, m), 6.76 (1 H, d, J=9.6 Hz), 6.85 (1 H, d, J=8.7 Hz), 6.99 (1 H, dd, J=8.7, 2.3 Hz), 7.03 (1 H, d, J=2.3 Hz), 7.08 (1 H, d, J=2.8 Hz), 7.86 (1 H, m), 8.29 (1 H, d, J=2.8 Hz) 1- (2- (4-((2,3-dihydrobenzo (1,4) dioxin-6-ylamino) methyl) -4-hydroxycyclohexylidene) ethyl) -7-methoxy-1H- (1,5 ) 1- (2- (3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) in the form of colorless foam by the same procedure as in Example 15 using 140 mg of naphthyridin-2-one There was obtained 107 mg of -2-oxo-1-oxa-3-azaspiro (4.5) decan-8-ylidene) ethyl) -7-methoxy-1H- (1,5) -naphthyridin-2-one.
1H NMR (CHLOROFORM-d) δ 1.67-1.74 (1 H, m), 1.77-1.84 (1 H, m), 2.07-2.12 (1 H, m), 2.16 (1 H, dt, J = 13.8, 4.4 Hz), 2.22 (1 H, ddt, J = 9.1, 6.8, 4.4, 4.4 Hz), 2.52-2.62 (2 H, m), 2.78 (1 H, dt, J = 13.8, 4.4 Hz), 3.65-3.72 (2 H, m), 3.97 (3 H, s), 4.22-4.27 (4 H, m), 4.57 (1 H, dd, J = 14.9, 5.7 Hz), 5.21-5.30 (2 H, m), 6.76 (1 H, d, J = 9.6 Hz), 6.85 (1 H, d, J = 8.7 Hz), 6.99 (1 H, dd, J = 8.7, 2.3 Hz), 7.03 (1 H, d, J = 2.3 Hz), 7.08 (1 H, d, J = 2.8 Hz), 7.86 (1 H, m), 8.29 (1 H, d, J = 2.8 Hz)
実施例１９
Figure JPOXMLDOC01-appb-I000103
Example 19
Figure JPOXMLDOC01-appb-I000103
１－（２－（４－（（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イルアミノ）メチル）－４－ヒドロキシシクロヘキシリデン）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン3mgを用いて、実施例１５と同様の操作により、無色泡状の１－（２－（３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）－２－オキソ－１－オキサ－３－アザスピロ（４．５）デカン－８－イリデン）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン3mgを得た。
1H NMR (CHLOROFORM-d)δ 1.69 - 1.77 (1 H, m), 1.83 (1 H, ddd, J=13.6, 11.1, 4.6 Hz), 2.02 - 2.09 (1 H, m), 2.12 - 2.22 (2 H, m), 2.48 - 2.58 (1 H, m), 2.59 - 2.66 (1 H, m), 2.67 - 2.74 (1 H, m), 3.95 (2 H, q, J=10.1 Hz), 4.24 - 4.29 (2 H, m), 4.32 - 4.36 (2 H, m), 4.72 (1 H, dd, J=15.6, 6.0 Hz), 5.06 (1 H, dd, J=15.6, 6.4 Hz), 5.21 (1 H, t, J=6.4 Hz), 6.88 (1 H, d, J=9.6 Hz), 7.31 (1 H, dd, J=10.1, 2.3 Hz), 7.78 (1 H, s), 7.87 (1 H, s), 7.89 (1 H, d, J=9.6 Hz), 8.43 (1 H, d, J=2.3 Hz) 1- (2- (4-((2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-ylamino) methyl) -4-hydroxycyclohexylidene) ethyl) -7- Using the same procedure as in Example 15 using 3 mg of fluoro-1H- (1,5) naphthyridin-2-one, colorless foamy 1- (2- (3- (2,3-dihydro- (1, 4) Dioxino (2,3-c) pyridin-7-yl) -2-oxo-1-oxa-3-azaspiro (4.5) decan-8-ylidene) ethyl) -7-fluoro-1H- (1 , 5) 3 mg of naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.69-1.77 (1 H, m), 1.83 (1 H, ddd, J = 13.6, 11.1, 4.6 Hz), 2.02-2.09 (1 H, m), 2.12-2.22 (2 H, m), 2.48-2.58 (1 H, m), 2.59-2.66 (1 H, m), 2.67-2.74 (1 H, m), 3.95 (2 H, q, J = 10.1 Hz), 4.24- 4.29 (2 H, m), 4.32-4.36 (2 H, m), 4.72 (1 H, dd, J = 15.6, 6.0 Hz), 5.06 (1 H, dd, J = 15.6, 6.4 Hz), 5.21 ( 1 H, t, J = 6.4 Hz), 6.88 (1 H, d, J = 9.6 Hz), 7.31 (1 H, dd, J = 10.1, 2.3 Hz), 7.78 (1 H, s), 7.87 (1 H, s), 7.89 (1 H, d, J = 9.6 Hz), 8.43 (1 H, d, J = 2.3 Hz)
実施例２０
Figure JPOXMLDOC01-appb-I000104
Example 20
Figure JPOXMLDOC01-appb-I000104
６－（（４－（２－（７－フルオロ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）エチリデン）－１－ヒドロキシシクロヘキシルメチル）アミノ）－４Ｈ－ベンゾ（１，４）オキサジン－３－オン30mgを用いて、実施例１５と同様の操作により、無色粉状の６－（８－（２－（７－フルオロ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）エチリデン）－２－オキソ－１－オキサ－３－アザスピロ（４．５）デカン－３－イル）－４Ｈ－ベンゾ（１，４）オキサジン－３－オン15mgを得た。
1H NMR (DMSO-d6)δ 1.73 - 1.80 (1 H, m), 1.82 - 1.91 (2 H, m), 1.97 - 2.03 (1 H, m), 2.13 - 2.20 (1 H, m), 2.25 - 2.32 (1 H, m), 2.60 - 2.67 (2 H, m), 3.79 - 3.88 (2 H, m), 4.54 (2 H, s), 4.85 (1 H, dd, J=15.6, 6.4 Hz), 4.93 - 5.00 (1 H, m), 5.21 (1 H, t, J=6.9 Hz), 6.86 (1 H, d, J=9.2 Hz), 6.90 - 6.93 (1 H, m), 6.95 - 6.97 (1 H, m), 7.39 (1 H, d, J=2.8 Hz), 7.85 (1 H, dd, J=11.0, 2.3 Hz), 7.96 (1 H, d, J=9.2 Hz), 8.58 (1 H, d, J=2.3 Hz), 10.74 (1 H, s) 6-((4- (2- (7-Fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) ethylidene) -1-hydroxycyclohexylmethyl) amino) -4H-benzo (1,4 ) 6- (8- (2- (7-Fluoro-2-oxo-2H- (1,5) naphthyridine-) in the form of colorless powder by the same operation as in Example 15 using 30 mg of oxazin-3-one 15 mg of 1-yl) ethylidene) -2-oxo-1-oxa-3-azaspiro (4.5) decan-3-yl) -4H-benzo (1,4) oxazin-3-one were obtained.
1H NMR (DMSO-d6) δ 1.73-1.80 (1 H, m), 1.82-1.91 (2 H, m), 1.97-2.03 (1 H, m), 2.13-2.20 (1 H, m), 2.25- 2.32 (1 H, m), 2.60-2.67 (2 H, m), 3.79-3.88 (2 H, m), 4.54 (2 H, s), 4.85 (1 H, dd, J = 15.6, 6.4 Hz) , 4.93-5.00 (1 H, m), 5.21 (1 H, t, J = 6.9 Hz), 6.86 (1 H, d, J = 9.2 Hz), 6.90-6.93 (1 H, m), 6.95-6.97 (1 H, m), 7.39 (1 H, d, J = 2.8 Hz), 7.85 (1 H, dd, J = 11.0, 2.3 Hz), 7.96 (1 H, d, J = 9.2 Hz), 8.58 ( 1 H, d, J = 2.3 Hz), 10.74 (1 H, s)
実施例２１
Figure JPOXMLDOC01-appb-I000105
Example 21
Figure JPOXMLDOC01-appb-I000105
７－フルオロ－１－（２－（４－（（３－フルオロ－４－メチルフェニルアミノ）メチル）－４－ヒドロキシシクロヘキシリデン）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン80mgを用いて、実施例１５と同様の操作により、白色固体状の７－フルオロ－１－（２－（３－（３－フルオロ－４－メチルフェニル）－２－オキソ－１－オキサ－３－アザスピロ（４．５）デカン－８－イリデン）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン82mgを得た。
1H NMR (CHLOROFORM-d)δ 1.71 (1 H, td, J=12.6, 4.6 Hz), 1.78 - 1.84 (1 H, m), 2.10 (1 H, dtd, J=13.5, 4.4, 4.4, 2.5 Hz), 2.14 - 2.19 (1 H, m), 2.20 - 2.23 (1 H, m), 2.24 (3 H, d, J=1.4 Hz), 2.53 - 2.63 (2 H, m), 2.76 (1 H, dt, J=14.1, 4.4 Hz), 3.67 - 3.71 (1 H, m), 3.72 - 3.75 (1 H, m), 4.65 (1 H, dd, J=15.6, 5.5 Hz), 5.12 (1 H, dd, J=15.6, 6.9 Hz), 5.22 (1 H, t, J=6.4 Hz), 6.87 (1 H, d, J=9.6 Hz), 7.10 - 7.13 (1 H, m), 7.13 - 7.17 (1 H, m), 7.31 (1 H, dd, J=10.1, 2.3 Hz), 7.36 (1 H, dd, J=11.7, 2.1 Hz), 7.89 (1 H, d, J=9.6 Hz), 8.43 (1 H, d, J=2.3 Hz) 7-fluoro-1- (2- (4-((3-fluoro-4-methylphenylamino) methyl) -4-hydroxycyclohexylidene) ethyl) -1H- (1,5) naphthyridin-2-one 80 mg Was used in the same manner as in Example 15 to obtain white solid 7-fluoro-1- (2- (3- (3-fluoro-4-methylphenyl) -2-oxo-1-oxa-3- 82 mg of azaspiro (4.5) decan-8-ylidene) ethyl) -1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.71 (1 H, td, J = 12.6, 4.6 Hz), 1.78-1.84 (1 H, m), 2.10 (1 H, dtd, J = 13.5, 4.4, 4.4, 2.5 Hz ), 2.14-2.19 (1 H, m), 2.20-2.23 (1 H, m), 2.24 (3 H, d, J = 1.4 Hz), 2.53-2.63 (2 H, m), 2.76 (1 H, dt, J = 14.1, 4.4 Hz), 3.67-3.71 (1 H, m), 3.72-3.75 (1 H, m), 4.65 (1 H, dd, J = 15.6, 5.5 Hz), 5.12 (1 H, dd, J = 15.6, 6.9 Hz), 5.22 (1 H, t, J = 6.4 Hz), 6.87 (1 H, d, J = 9.6 Hz), 7.10-7.13 (1 H, m), 7.13-7.17 ( 1 H, m), 7.31 (1 H, dd, J = 10.1, 2.3 Hz), 7.36 (1 H, dd, J = 11.7, 2.1 Hz), 7.89 (1 H, d, J = 9.6 Hz), 8.43 (1 H, d, J = 2.3 Hz)
実施例２２
Figure JPOXMLDOC01-appb-I000106
Example 22
Figure JPOXMLDOC01-appb-I000106
１－（２－（３，９－ジアザスピロ（５．５）ウンデカン－３－イル）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オンの塩酸塩20mg及び７－クロロメチル－２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジンの塩酸塩13mgをテトラヒドロフラン2mL－Ｎ，Ｎ－ジメチルホルムアミド2mLに懸濁し、炭酸カリウム33mgを加えて、８０℃にて１８時間撹拌した。反応混合物に水5mL、酢酸エチル50mL及びトルエン10mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液5mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア株式会社、Chromatorex-NH、溶離液；クロロホルム：メタノール＝９：１］で精製し、１－（２－（９－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イルメチル）－３，９－ジアザスピロ（５．５）ウンデカン－３－イル）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン17mgを得た。
1H NMR (CHLOROFORM-d)δ 1.47 - 1.57 (8 H, m), 2.39 - 2.58 (8 H, m), 2.61 - 2.67 (2 H, m), 3.52 (2 H, s), 4.25 - 4.36 (6 H, m), 6.86 (1 H, d, J=9.6 Hz), 6.90 (1 H, s), 7.56 (1 H, dd, J=10.1, 2.3 Hz), 7.88 (1 H, d, J=9.6 Hz), 8.11 (1 H, s), 8.41 (1 H, d, J=2.3 Hz) 1- (2- (3,9-diazaspiro (5.5) undecan-3-yl) ethyl) -7-fluoro-1H- (1,5) naphthyridin-2-one hydrochloride 20 mg and 7-chloromethyl -2,3-dihydro- (1,4) dioxyno (2,3-c) pyridine hydrochloride 13 mg was suspended in tetrahydrofuran 2 mL-N, N-dimethylformamide 2 mL, potassium carbonate 33 mg was added, and the mixture was heated to 80 ° C. And stirred for 18 hours. Water (5 mL), ethyl acetate (50 mL) and toluene (10 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with 5 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Co., Ltd., Chromatorex-NH, eluent: chloroform: methanol = 9: 1] to give 1- (2- (9- (2,3- Dihydro- (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) -3,9-diazaspiro (5.5) undecan-3-yl) ethyl) -7-fluoro-1H- (1, 5) 17 mg of naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.47-1.57 (8 H, m), 2.39-2.58 (8 H, m), 2.61-2.67 (2 H, m), 3.52 (2 H, s), 4.25-4.36 ( 6 H, m), 6.86 (1 H, d, J = 9.6 Hz), 6.90 (1 H, s), 7.56 (1 H, dd, J = 10.1, 2.3 Hz), 7.88 (1 H, d, J = 9.6 Hz), 8.11 (1 H, s), 8.41 (1 H, d, J = 2.3 Hz)
実施例２３
Figure JPOXMLDOC01-appb-I000107
Example 23
Figure JPOXMLDOC01-appb-I000107
１－（２－（２，７－ジアザスピロ（４．４）ノナ－２－イル）エチル）－７－フルオロ－１Ｈ－（１，５）－ナフチリジン－２－オンの塩酸塩30mgをクロロホルム3mLに懸濁し、トリエチルアミン33μLを加えて溶解させた。２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－カルバルデヒド13mgのクロロホルム溶液2mLを加え、５５℃で３時間撹拌した。反応混合物を氷冷し、トリアセトキシ水素化ホウ素ナトリウム53mgを加え、室温で３時間撹拌した。反応混合物を減圧下溶媒留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア株式会社、Chromatorex-NH、溶離液；クロロホルム：メタノール＝９６：４］で精製して、黄色油状の１－（２－（７－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イルメチル）－２，７－ジアザスピロ（４．４）ノナ－２－イル）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン18mgを得た。
1H NMR (CHLOROFORM-d)δ 1.76 - 1.94 (4 H, m), 2.50 (1 H, d, J=9.2 Hz), 2.56 - 2.81 (9 H, m), 3.60 - 3.69 (2 H, m), 4.25 - 4.36 (6 H, m), 6.86 (1 H, d, J=9.6 Hz), 6.91 (1 H, s), 7.56 (1 H, dd, J=10.3, 2.1 Hz), 7.88 (1 H, d, J=9.6 Hz), 8.09 (1 H, s), 8.40 (1 H, d, J=2.1 Hz) 30 mg of 1- (2- (2,7-diazaspiro (4.4) non-2-yl) ethyl) -7-fluoro-1H- (1,5) -naphthyridin-2-one hydrochloride was added to 3 mL of chloroform. Suspended and dissolved by adding 33 μL of triethylamine. 2,3-Dihydro- (1,4) dioxyno (2,3-c) pyridine-7-carbaldehyde (13 mg) in chloroform (2 mL) was added, and the mixture was stirred at 55 ° C. for 3 hours. The reaction mixture was ice-cooled, 53 mg of sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Ltd., Chromatorex-NH, eluent: chloroform: methanol = 96: 4] to give a yellow oil 1- (2- (7- (2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) -2,7-diazaspiro (4.4) nona-2- Yl) ethyl) -7-fluoro-1H- (1,5) naphthyridin-2-one (18 mg) was obtained.
1H NMR (CHLOROFORM-d) δ 1.76-1.94 (4 H, m), 2.50 (1 H, d, J = 9.2 Hz), 2.56-2.81 (9 H, m), 3.60-3.69 (2 H, m) , 4.25-4.36 (6 H, m), 6.86 (1 H, d, J = 9.6 Hz), 6.91 (1 H, s), 7.56 (1 H, dd, J = 10.3, 2.1 Hz), 7.88 (1 H, d, J = 9.6 Hz), 8.09 (1 H, s), 8.40 (1 H, d, J = 2.1 Hz)
実施例２４
Figure JPOXMLDOC01-appb-I000108
Example 24
Figure JPOXMLDOC01-appb-I000108
１－（２－（２，３－ジヒドロ－１Ｈ－スピロ（イソキノリン－４，４’－ピペリジン）－１’－イル）エチル）－７－フルオロ－（１，５）－ナフチリジン－２（１Ｈ）－オンの塩酸塩100mg及び２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－カルバルデヒド39mgを用いて、実施例２３と同様の操作により、淡黄色油状の１－（２－（２－（（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）メチル）－２，３－ジヒドロ－１Ｈ－スピロ（イソキノリン－４，４’－ピペリジン）－１’－イル）エチル）－７－フルオロ－（１，５）－ナフチリジン－２（１Ｈ）－オン73mgを得た。
1H NMR (CHLOROFORM-d)δ 1.81 - 1.89 (2 H, m), 2.01 - 2.12 (2 H, m), 2.20 (2 H, t, J=11.5 Hz), 2.63 (2 H, t, J=6.9 Hz), 2.70 (2 H, s), 2.79 - 2.88 (2 H, m), 3.68 (2 H, s), 3.71 (2 H, s), 4.27 - 4.30 (2 H, m), 4.31 - 4.38 (4 H, m), 6.87 (1 H, d, J=9.6 Hz), 6.97 - 7.02 (2 H, m), 7.09 - 7.15 (1 H, m), 7.21 (1 H, t, J=7.8 Hz), 7.40 (1 H, d, J=7.8 Hz), 7.62 (1 H, d, J=9.2 Hz), 7.90 (1 H, d, J=9.6 Hz), 8.11 (1 H, s), 8.44 (1 H, d, J=2.3 Hz) 1- (2- (2,3-dihydro-1H-spiro (isoquinoline-4,4′-piperidin) -1′-yl) ethyl) -7-fluoro- (1,5) -naphthyridine-2 (1H) Using a procedure similar to that of Example 23 using 100 mg of -one hydrochloride and 39 mg of 2,3-dihydro- (1,4) dioxyno (2,3-c) pyridine-7-carbaldehyde, 1- (2- (2-((2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-yl) methyl) -2,3-dihydro-1H-spiro (isoquinoline- 73 mg of 4,4′-piperidin) -1′-yl) ethyl) -7-fluoro- (1,5) -naphthyridin-2 (1H) -one was obtained.
1H NMR (CHLOROFORM-d) δ 1.81-1.89 (2 H, m), 2.01-2.12 (2 H, m), 2.20 (2 H, t, J = 11.5 Hz), 2.63 (2 H, t, J = 6.9 Hz), 2.70 (2 H, s), 2.79-2.88 (2 H, m), 3.68 (2 H, s), 3.71 (2 H, s), 4.27-4.30 (2 H, m), 4.31- 4.38 (4 H, m), 6.87 (1 H, d, J = 9.6 Hz), 6.97-7.02 (2 H, m), 7.09-7.15 (1 H, m), 7.21 (1 H, t, J = 7.8 Hz), 7.40 (1 H, d, J = 7.8 Hz), 7.62 (1 H, d, J = 9.2 Hz), 7.90 (1 H, d, J = 9.6 Hz), 8.11 (1 H, s) , 8.44 (1 H, d, J = 2.3 Hz)
実施例２５
Figure JPOXMLDOC01-appb-I000109
Example 25
Figure JPOXMLDOC01-appb-I000109
１－（２－（２，８－ジアザスピロ（４．５）デカン－８－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オンの塩酸塩91mg、６－ブロモ－２，３－ジヒドロベンゾ（１，４）ジオキシン43mg、ｔｅｒｔ－ブトキシカリウム90mg、酢酸パラジウム0.2mg、及び２－（ジシクロヘキシルホスフィノ）ビフェニル0.7mgをトリフルオロメチルベンゼン4mLに懸濁し、マイクロウェーブにて１５０℃、２０分撹拌した。反応混合物を減圧下溶媒留去して、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア株式会社、Chromatorex-NH、溶離液；酢酸エチル：ヘキサン＝４：１］及び分取用シリカゲル薄層クロマトグラフィーＮＨタイプ［富士シリシア株式会社製ＰＬＣプレートＮＨ、展開液；酢酸エチル）］で精製し、黄色油状の１－（２－（２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２，８－ジアザスピロ（４．５）デカン－８－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン12mgを得た。
1H NMR (CHLOROFORM-d)δ 1.60 - 1.69 (4 H, m), 1.84 (2 H, t, J=6.9 Hz), 2.51 (2 H, br. s.), 2.62 - 2.69 (4 H, m), 3.07 (2 H, s), 3.27 (2 H, t, J=6.9 Hz), 3.98 (3 H, s), 4.17 - 4.20 (2 H, m), 4.23 - 4.25 (2 H, m), 4.38 (2 H, t, J=7.3 Hz), 6.06 - 6.09 (2 H, m), 6.74 - 6.77 (2 H, m), 7.21 (1 H, d, J=2.3 Hz), 7.85 (1 H, d, J=9.6 Hz), 8.28 (1 H, d, J=2.3 Hz) 1- (2- (2,8-diazaspiro (4.5) decan-8-yl) ethyl) -7-methoxy-1H- (1,5) naphthyridin-2-one hydrochloride 91 mg, 6-bromo- 2,3-dihydrobenzo (1,4) dioxin 43 mg, tert-butoxypotassium 90 mg, palladium acetate 0.2 mg, and 2- (dicyclohexylphosphino) biphenyl 0.7 mg were suspended in 4 mL of trifluoromethylbenzene, and microwaved. The mixture was stirred at 150 ° C. for 20 minutes. The reaction mixture was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [silica gel; Fuji Silysia Ltd., Chromatorex-NH, eluent: ethyl acetate: hexane = 4: 1] and preparative silica gel. Purified by thin layer chromatography NH type [PLC plate NH manufactured by Fuji Silysia Ltd., developing solution: ethyl acetate]] and purified as 1- (2- (2- (2,3-dihydrobenzo (1,4)) Dioxin-6-yl) -2,8-diazaspiro (4.5) decan-8-yl) ethyl) -7-methoxy-1H- (1,5) naphthyridin-2-one 12 mg was obtained.
1H NMR (CHLOROFORM-d) δ 1.60-1.69 (4 H, m), 1.84 (2 H, t, J = 6.9 Hz), 2.51 (2 H, br.s.), 2.62-2.69 (4 H, m ), 3.07 (2 H, s), 3.27 (2 H, t, J = 6.9 Hz), 3.98 (3 H, s), 4.17-4.20 (2 H, m), 4.23-4.25 (2 H, m) , 4.38 (2 H, t, J = 7.3 Hz), 6.06-6.09 (2 H, m), 6.74-6.77 (2 H, m), 7.21 (1 H, d, J = 2.3 Hz), 7.85 (1 H, d, J = 9.6 Hz), 8.28 (1 H, d, J = 2.3 Hz)
実施例２６
Figure JPOXMLDOC01-appb-I000110
Example 26
Figure JPOXMLDOC01-appb-I000110
７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒド188mgをクロロホルム12mLに溶解し、３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン275mg及びメタノール0.5mLを加えて、室温にて５時間撹拌した。酢酸50μL及びトリアセトキシ水素化ホウ素ナトリウム384mgを加えて、室温にて２．５時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液15mLを加えて、有機層を分取した。有機層を飽和塩化ナトリウム水溶液5mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア株式会社、Chromatorex-NH、溶離液；酢酸エチル：ヘキサン＝９８：２］で精製して、白色泡状の１－（２－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン330mgを得た。
1H NMR (CHLOROFORM-d)δ 1.83 - 1.89 (2 H, m), 2.01 - 2.05 (2 H, m), 2.70 - 2.78 (6 H, m), 3.68 (2 H, s), 3.99 (3 H, s), 4.23 - 4.27 (4 H, m), 4.39 (2 H, t, J=7.1 Hz), 6.75 (1 H, d, J=9.6 Hz), 6.85 (1 H, d, J=8.7 Hz), 6.99 (1 H, dd, J=8.7, 2.8 Hz), 7.07 (1 H, d, J=2.8 Hz), 7.15 (1 H, br. s.), 7.85 (1 H, d, J=9.6 Hz), 8.29 (1 H, d, J=2.8 Hz) 7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde (188 mg) was dissolved in chloroform (12 mL) to give 3- (2,3-dihydrobenzo (1,4) dioxin-6-yl). 275 mg of 1-oxa-3,8-diazaspiro (4.5) decan-2-one and 0.5 mL of methanol were added and stirred at room temperature for 5 hours. 50 μL of acetic acid and 384 mg of sodium triacetoxyborohydride were added and stirred at room temperature for 2.5 hours. To the reaction mixture, 15 mL of a saturated aqueous sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with 5 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Ltd., Chromatorex-NH, eluent; ethyl acetate: hexane = 98: 2] to give 1- (2- (3 -(2,3-dihydrobenzo (1,4) dioxin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-yl) ethyl) -7-methoxy 330 mg of -1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.83-1.89 (2 H, m), 2.01-2.05 (2 H, m), 2.70-2.78 (6 H, m), 3.68 (2 H, s), 3.99 (3 H , s), 4.23-4.27 (4 H, m), 4.39 (2 H, t, J = 7.1 Hz), 6.75 (1 H, d, J = 9.6 Hz), 6.85 (1 H, d, J = 8.7 Hz), 6.99 (1 H, dd, J = 8.7, 2.8 Hz), 7.07 (1 H, d, J = 2.8 Hz), 7.15 (1 H, br.s.), 7.85 (1 H, d, J = 9.6 Hz), 8.29 (1 H, d, J = 2.8 Hz)
実施例２７
Figure JPOXMLDOC01-appb-I000111
Example 27
Figure JPOXMLDOC01-appb-I000111
３－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）プロピオンアルデヒド86mg及び３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン118mgを用いて、実施例２６と同様の操作により、無色油状の１－（３－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－イル）プロピル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン82mgを得た。
1H NMR (CHLOROFORM-d)δ 1.87 (2 H, dt, J=13.4, 6.8 Hz), 1.93 (2 H, quin, J=7.0 Hz), 2.01 - 2.06 (2 H, m), 2.52 (2 H, t, J=6.6 Hz), 2.61 (4 H, br. s.), 3.68 (2 H, s), 3.99 (3 H, s), 4.23 - 4.27 (4 H, m), 4.30 (2 H, t, J=7.3 Hz), 6.76 (1 H, d, J=9.6 Hz), 6.85 (1 H, d, J=9.2 Hz), 6.98 - 7.01 (1 H, m), 7.07 (1 H, d, J=2.8 Hz), 7.24 (1 H, d, J=2.3 Hz), 7.85 (1 H, d, J=9.6 Hz), 8.29 (1 H, d, J=2.3 Hz) 3- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) propionaldehyde 86 mg and 3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1 Using 1- (3- (3- (2,3-dihydrobenzoic acid) of colorless oil by the same procedure as in Example 26 using 118 mg of -oxa-3,8-diazaspiro (4.5) decan-2-one (1,4) dioxin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-yl) propyl) -7-methoxy-1H- (1,5) 82 mg of naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.87 (2 H, dt, J = 13.4, 6.8 Hz), 1.93 (2 H, quin, J = 7.0 Hz), 2.01-2.06 (2 H, m), 2.52 (2 H , t, J = 6.6 Hz), 2.61 (4 H, br.s.), 3.68 (2 H, s), 3.99 (3 H, s), 4.23-4.27 (4 H, m), 4.30 (2 H , t, J = 7.3 Hz), 6.76 (1 H, d, J = 9.6 Hz), 6.85 (1 H, d, J = 9.2 Hz), 6.98-7.01 (1 H, m), 7.07 (1 H, d, J = 2.8 Hz), 7.24 (1 H, d, J = 2.3 Hz), 7.85 (1 H, d, J = 9.6 Hz), 8.29 (1 H, d, J = 2.3 Hz)
実施例２８
Figure JPOXMLDOC01-appb-I000112
Example 28
Figure JPOXMLDOC01-appb-I000112
（２－オキソ－２Ｈ－（１，７）ナフチリジン－１－イル）アセトアルデヒド90mg及び３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン153mgを用いて、実施例２６と同様の操作により、淡橙色固体状の１－（２－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－イル）エチル）－１Ｈ－（１，７）ナフチリジン－２－オン100mgを得た。
1H NMR (CHLOROFORM-d)δ 1.84 (2 H, dt, J=13.5, 7.0 Hz), 2.02 (2 H, d, J=13.3 Hz), 2.72 - 2.81 (6 H, m), 3.67 (2 H, s), 4.23 - 4.27 (4 H, m), 4.49 (2 H, t, J=7.1 Hz), 6.85 (1 H, d, J=8.7 Hz), 6.90 (1 H, d, J=9.2 Hz), 6.99 (1 H, dd, J=8.7, 2.8 Hz), 7.07 (1 H, d, J=2.3 Hz), 7.43 (1 H, d, J=5.0 Hz), 7.66 (1 H, d, J=9.2 Hz), 8.46 (1 H, d, J=5.0 Hz), 8.90 (1 H, s) 90 mg of (2-oxo-2H- (1,7) naphthyridin-1-yl) acetaldehyde and 3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxa-3,8- 1- (2- (3- (2,3-dihydrobenzo (1,4)) of pale orange solid was prepared in the same manner as in Example 26 using 153 mg of diazaspiro (4.5) decan-2-one. 100 mg of dioxin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-yl) ethyl) -1H- (1,7) naphthyridin-2-one was obtained. .
1H NMR (CHLOROFORM-d) δ 1.84 (2 H, dt, J = 13.5, 7.0 Hz), 2.02 (2 H, d, J = 13.3 Hz), 2.72-2.81 (6 H, m), 3.67 (2 H , s), 4.23-4.27 (4 H, m), 4.49 (2 H, t, J = 7.1 Hz), 6.85 (1 H, d, J = 8.7 Hz), 6.90 (1 H, d, J = 9.2 Hz), 6.99 (1 H, dd, J = 8.7, 2.8 Hz), 7.07 (1 H, d, J = 2.3 Hz), 7.43 (1 H, d, J = 5.0 Hz), 7.66 (1 H, d , J = 9.2 Hz), 8.46 (1 H, d, J = 5.0 Hz), 8.90 (1 H, s)
実施例２９
Figure JPOXMLDOC01-appb-I000113
Example 29
Figure JPOXMLDOC01-appb-I000113
２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，７－ジアザスピロ（３．５）ノナ－１－オンの塩酸塩30mgをクロロホルム1.5mLに懸濁し、トリエチルアミン67μLを加えて溶解させた。３－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）プロピオンアルデヒド21mg及び酢酸22μLを加え、室温にて１．５時間撹拌した。反応混合物を氷冷し、トリアセトキシ水素化ホウ素ナトリウム43mgを加え、室温に戻して３時間撹拌した。反応混合物を減圧下溶媒留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル］で精製し、黄色固体状の１－（２－（２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，７－ジアザスピロ（３．５）ノナ－７－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン32mgを得た。
1H NMR (CHLOROFORM-d)δ 1.86 - 1.93 (2 H, m), 2.10 (2 H, ddd, J=13.2, 9.1, 3.4 Hz), 2.52 (2 H, br. s.), 2.73 (2 H, t, J=7.3 Hz), 2.98 - 3.03 (2 H, m), 3.40 (2 H, s), 4.00 (3 H, s), 4.21 - 4.26 (4 H, m), 4.41 (2 H, t, J=7.3 Hz), 6.75 (1 H, d, J=9.6 Hz), 6.80 - 6.83 (1 H, m), 6.84 - 6.87 (1 H, m), 6.88 (1 H, d, J=2.3 Hz), 7.26 (1 H, d, J=2.3 Hz), 7.86 (1 H, d, J=9.6 Hz), 8.29 (1 H, d, J=2.3 Hz) Suspend 30 mg of 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxo-2,7-diazaspiro (3.5) non-1-one hydrochloride in 1.5 mL of chloroform. It became cloudy and 67 μL of triethylamine was added and dissolved. 3- (7-Methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) propionaldehyde (21 mg) and acetic acid (22 μL) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was ice-cooled, 43 mg of sodium triacetoxyborohydride was added, and the mixture was allowed to warm to room temperature and stirred for 3 hr. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: ethyl acetate] to give 1- (2- (2- (2,3-Dihydrobenzo (1,4) dioxin-6-yl) -1-oxo-2,7-diazaspiro (3.5) non-7-yl) ethyl) -7-methoxy-1H 32 mg of (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.86-1.93 (2 H, m), 2.10 (2 H, ddd, J = 13.2, 9.1, 3.4 Hz), 2.52 (2 H, br.s.), 2.73 (2 H , t, J = 7.3 Hz), 2.98-3.03 (2 H, m), 3.40 (2 H, s), 4.00 (3 H, s), 4.21-4.26 (4 H, m), 4.41 (2 H, t, J = 7.3 Hz), 6.75 (1 H, d, J = 9.6 Hz), 6.80-6.83 (1 H, m), 6.84-6.87 (1 H, m), 6.88 (1 H, d, J = 2.3 Hz), 7.26 (1 H, d, J = 2.3 Hz), 7.86 (1 H, d, J = 9.6 Hz), 8.29 (1 H, d, J = 2.3 Hz)
実施例３０
Figure JPOXMLDOC01-appb-I000114
Example 30
Figure JPOXMLDOC01-appb-I000114
３－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒド29.9mg及び２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－３－オン38.4mgを用いて、実施例２６と同様の操作により、１－（２－（２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－８－イル）エチル）－７－メトキシ－１Ｈ－（１，５）－ナフチリジン－２－オン45mgを得た。
1H NMR (CHLOROFORM-d)δ 1.73 (4 H, t, J=5.5 Hz), 2.47 (2 H, s), 2.50 - 2.59 (2 H, m), 2.59 - 2.72 (4 H, m), 3.57 (2 H, s), 3.98 (3 H, s), 4.20 - 4.28 (4 H, m), 4.37 (2 H, t, J=7.3 Hz), 6.75 (1 H, d, J=9.6 Hz), 6.84 (1 H, d, J=9.2 Hz), 7.03 (1 H, dd, J=8.7, 2.8 Hz), 7.12 (1 H, s), 7.17 (1 H, d, J=2.3 Hz), 7.85 (1 H, d, J=9.6 Hz), 8.29 (1 H, d, J=2.8 Hz) 2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde 29.9 mg and 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -3 1- (2- (2- (2,3-dihydrobenzo (1)) was obtained in the same manner as in Example 26 using 38.4 mg of -oxo-2,8-diazaspiro (4.5) decan-3-one. , 4) dioxin-6-yl) -3-oxo-2,8-diazaspiro (4.5) decan-8-yl) ethyl) -7-methoxy-1H- (1,5) -naphthyridin-2-one 45 mg was obtained.
1H NMR (CHLOROFORM-d) δ 1.73 (4 H, t, J = 5.5 Hz), 2.47 (2 H, s), 2.50-2.59 (2 H, m), 2.59-2.72 (4 H, m), 3.57 (2 H, s), 3.98 (3 H, s), 4.20-4.28 (4 H, m), 4.37 (2 H, t, J = 7.3 Hz), 6.75 (1 H, d, J = 9.6 Hz) , 6.84 (1 H, d, J = 9.2 Hz), 7.03 (1 H, dd, J = 8.7, 2.8 Hz), 7.12 (1 H, s), 7.17 (1 H, d, J = 2.3 Hz), 7.85 (1 H, d, J = 9.6 Hz), 8.29 (1 H, d, J = 2.8 Hz)
実施例３１
Figure JPOXMLDOC01-appb-I000115
Example 31
Figure JPOXMLDOC01-appb-I000115
３－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）プロピオンアルデヒド35mg及び２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－３－オン41mgを用いて、実施例２６と同様の操作により、１－（３－（２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－８－イル）プロピル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン56mgを得た。
1H NMR (CHLOROFORM-d)δ 1.73 (4 H, t, J=5.5 Hz), 1.92 (2 H, quin, J=6.9 Hz), 2.34 - 2.57 (8 H, m), 3.56 (2 H, s), 3.99 (3 H, s), 4.21 - 4.27 (4 H, m), 4.27 - 4.32 (2 H, m), 6.75 (1 H, d, J=9.6 Hz), 6.85 (1 H, d, J=8.7 Hz), 7.04 (1 H, dd, J=8.7, 2.3 Hz), 7.13 (1 H, d, J=2.3 Hz), 7.20 - 7.25 (1 H, m), 7.84 (1 H, d, J=9.6 Hz), 8.28 (1 H, d, J=2.3 Hz) 3- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) propionaldehyde 35 mg and 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -3 1- (3- (2- (2,3-dihydrobenzo (1,1) -oxo-2,8-diazaspiro (4.5) decan-3-one was obtained in the same manner as in Example 26 using 41 mg. 4) 56 mg of dioxin-6-yl) -3-oxo-2,8-diazaspiro (4.5) decan-8-yl) propyl) -7-methoxy-1H- (1,5) naphthyridin-2-one Obtained.
1H NMR (CHLOROFORM-d) δ 1.73 (4 H, t, J = 5.5 Hz), 1.92 (2 H, quin, J = 6.9 Hz), 2.34-2.57 (8 H, m), 3.56 (2 H, s ), 3.99 (3 H, s), 4.21-4.27 (4 H, m), 4.27-4.32 (2 H, m), 6.75 (1 H, d, J = 9.6 Hz), 6.85 (1 H, d, J = 8.7 Hz), 7.04 (1 H, dd, J = 8.7, 2.3 Hz), 7.13 (1 H, d, J = 2.3 Hz), 7.20-7.25 (1 H, m), 7.84 (1 H, d , J = 9.6 Hz), 8.28 (1 H, d, J = 2.3 Hz)
実施例３２
Figure JPOXMLDOC01-appb-I000116
Example 32
Figure JPOXMLDOC01-appb-I000116
７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒド58mg及び２－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イルメチル）－２，８－ジアザスピロ（４．５）デカン－３－オンの塩酸塩118mgを用いて、実施例２９と同様の操作により、白色泡状の１－（２－（２－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イルメチル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－８－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン50mgを得た。
1H NMR (CHLOROFORM-d)δ 1.64 (4 H, br. s.), 2.32 (2 H, s), 2.52 (4 H, br. s.), 2.61 - 2.65 (2 H, m), 3.18 (2 H, s), 3.72 (2 H, q, J=7.2 Hz), 3.97 (3 H, s), 4.27 - 4.30 (2 H, m), 4.32 (2 H, td, J=3.8, 2.1 Hz), 4.44 (2 H, s), 6.74 (1 H, d, J=9.6 Hz), 6.76 (1 H, s), 7.16 (1 H, d, J=2.3 Hz), 7.84 (1 H, d, J=9.6 Hz), 8.08 (1 H, s), 8.28 (1 H, d, J=2.3 Hz) 7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde 58 mg and 2- (2,3-dihydro- (1,4) dioxino (2,3-c) pyridine-7- The white foamy 1- (2- (2- (2, 3-dihydro- (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) -3-oxo-2,8-diazaspiro (4.5) decan-8-yl) ethyl) -7-methoxy 50 mg of -1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.64 (4 H, br.s.), 2.32 (2 H, s), 2.52 (4 H, br.s.), 2.61-2.65 (2 H, m), 3.18 ( 2 H, s), 3.72 (2 H, q, J = 7.2 Hz), 3.97 (3 H, s), 4.27-4.30 (2 H, m), 4.32 (2 H, td, J = 3.8, 2.1 Hz ), 4.44 (2 H, s), 6.74 (1 H, d, J = 9.6 Hz), 6.76 (1 H, s), 7.16 (1 H, d, J = 2.3 Hz), 7.84 (1 H, d , J = 9.6 Hz), 8.08 (1 H, s), 8.28 (1 H, d, J = 2.3 Hz)
実施例３３
Figure JPOXMLDOC01-appb-I000117
Example 33
Figure JPOXMLDOC01-appb-I000117
（７－メトキシ－２－オキソ－２Ｈ－キノリン－１－イル）アセトアルデヒド98mg及び２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－３－オン41mgを用いて、実施例２６と同様の操作により、無色泡状の１－（２－（２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－８－イル）エチル）－７－メトキシ－１Ｈ－キノリン－２－オン98mgを得た。
1H NMR (CHLOROFORM-d)δ 1.76 (4 H, br. s.), 2.47 (2 H, s), 2.50 - 2.75 (6 H, m), 3.57 (2 H, s), 3.92 (3 H, s), 4.19 - 4.27 (4 H, m), 4.41 (2 H, t, J=7.6 Hz), 6.52 (1 H, d, J=9.2 Hz), 6.79 - 6.86 (2 H, m), 6.90 (1 H, s), 7.03 (1 H, dd, J=8.3, 2.3 Hz), 7.13 (1 H, d, J=2.8 Hz), 7.47 (1 H, d, J=8.3 Hz), 7.59 (1 H, d, J=9.2 Hz) 98 mg (7-methoxy-2-oxo-2H-quinolin-1-yl) acetaldehyde and 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -3-oxo-2,8-diazaspiro (4.5) colorless foamy 1- (2- (2- (2,3-dihydrobenzo (1,4) dioxin-) by the same procedure as in Example 26 using 41 mg of decan-3-one There were obtained 98 mg of 6-yl) -3-oxo-2,8-diazaspiro (4.5) decan-8-yl) ethyl) -7-methoxy-1H-quinolin-2-one.
1H NMR (CHLOROFORM-d) δ 1.76 (4 H, br.s.), 2.47 (2 H, s), 2.50-2.75 (6 H, m), 3.57 (2 H, s), 3.92 (3 H, s), 4.19-4.27 (4 H, m), 4.41 (2 H, t, J = 7.6 Hz), 6.52 (1 H, d, J = 9.2 Hz), 6.79-6.86 (2 H, m), 6.90 (1 H, s), 7.03 (1 H, dd, J = 8.3, 2.3 Hz), 7.13 (1 H, d, J = 2.8 Hz), 7.47 (1 H, d, J = 8.3 Hz), 7.59 ( (1 H, d, J = 9.2 Hz)
実施例３４
Figure JPOXMLDOC01-appb-I000118
Example 34
Figure JPOXMLDOC01-appb-I000118
７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒド70mg及び２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２，６－ジアザスピロ（３．５）－ノナン－１－オン83mgを用いて、実施例２６と同様の操作により、無色泡状の１－（２－（２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，６－ジアザスピロ（３．５）ノナ－６－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン84mgを得た。
1H NMR (CHLOROFORM-d)δ 1.80 - 1.85 (2 H, m), 1.86 - 1.93 (2 H, m), 2.08 - 2.14 (1 H, m), 2.44 - 2.55 (3 H, m), 2.74 - 2.80 (1 H, m), 2.85 - 2.91 (1 H, m), 3.39 (1 H, d, J=6.0 Hz), 3.51 (1 H, d, J=5.5 Hz), 3.94 (3 H, s), 4.19 - 4.27 (5 H, m), 4.31 - 4.38 (1 H, m), 6.74 (1 H, d, J=9.6 Hz), 6.80 - 6.83 (1 H, m), 6.85 - 6.90 (2 H, m), 7.19 (1 H, d, J=2.3 Hz), 7.84 (1 H, d, J=9.6 Hz), 8.28 (1 H, d, J=2.3 Hz) 7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde 70 mg and 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -2,6-diazaspiro A colorless foamy 1- (2- (2- (2,3-dihydrobenzo (1,4) dioxin) was prepared by the same procedure as in Example 26 using 83 mg of (3.5) -nonan-1-one. 84 mg of -6-yl) -1-oxo-2,6-diazaspiro (3.5) non-6-yl) ethyl) -7-methoxy-1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.80-1.85 (2 H, m), 1.86-1.93 (2 H, m), 2.08-2.14 (1 H, m), 2.44-2.55 (3 H, m), 2.74- 2.80 (1 H, m), 2.85-2.91 (1 H, m), 3.39 (1 H, d, J = 6.0 Hz), 3.51 (1 H, d, J = 5.5 Hz), 3.94 (3 H, s ), 4.19-4.27 (5 H, m), 4.31-4.38 (1 H, m), 6.74 (1 H, d, J = 9.6 Hz), 6.80-6.83 (1 H, m), 6.85-6.90 (2 H, m), 7.19 (1 H, d, J = 2.3 Hz), 7.84 (1 H, d, J = 9.6 Hz), 8.28 (1 H, d, J = 2.3 Hz)
実施例３５
Figure JPOXMLDOC01-appb-I000119
Example 35
Figure JPOXMLDOC01-appb-I000119
（７－メトキシ－２－オキソ－２Ｈ－キノリン－１－イル）アセトアルデヒド57mg及び３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン76mgを用いて、実施例２６と同様の操作により、白色固体状の１－（２－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－イル）エチル）－７－メトキシ－１Ｈ－キノリン－２－オン49mgを得た。
1H NMR (CHLOROFORM-d)δ 1.85 - 1.91 (2 H, m), 2.02 - 2.07 (2 H, m), 2.75 (6 H, m, J=15.8, 8.0 Hz), 3.69 (2 H, s), 3.92 (3 H, s), 4.23 - 4.27 (4 H, m), 4.39 - 4.43 (2 H, m), 6.53 (1 H, d, J=9.6 Hz), 6.83 (1 H, dd, J=8.3, 2.1 Hz), 6.85 (1 H, d, J=8.7 Hz), 6.87 (1 H, d, J=2.1 Hz), 6.99 (1 H, dd, J=8.7, 2.8 Hz), 7.08 (1 H, d, J=2.8 Hz), 7.47 (1 H, d, J=8.3 Hz), 7.59 (1 H, d, J=9.6 Hz) (7-Methoxy-2-oxo-2H-quinolin-1-yl) acetaldehyde 57 mg and 3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) 1-oxa-3,8-diazaspiro ( 4.5) 1- (2- (3- (2,3-dihydrobenzo (1,4) dioxin-6) in the form of a white solid was obtained in the same manner as in Example 26 using 76 mg of decan-2-one. There was obtained 49 mg of -yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-yl) ethyl) -7-methoxy-1H-quinolin-2-one.
1H NMR (CHLOROFORM-d) δ 1.85-1.91 (2 H, m), 2.02-2.07 (2 H, m), 2.75 (6 H, m, J = 15.8, 8.0 Hz), 3.69 (2 H, s) , 3.92 (3 H, s), 4.23-4.27 (4 H, m), 4.39-4.43 (2 H, m), 6.53 (1 H, d, J = 9.6 Hz), 6.83 (1 H, dd, J = 8.3, 2.1 Hz), 6.85 (1 H, d, J = 8.7 Hz), 6.87 (1 H, d, J = 2.1 Hz), 6.99 (1 H, dd, J = 8.7, 2.8 Hz), 7.08 ( 1 H, d, J = 2.8 Hz), 7.47 (1 H, d, J = 8.3 Hz), 7.59 (1 H, d, J = 9.6 Hz)
実施例３６
Figure JPOXMLDOC01-appb-I000120
Example 36
Figure JPOXMLDOC01-appb-I000120
（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒド39mg及び２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，９－ジアザスピロ（５．５）ウンデカン－１－オンの塩酸塩60mgを用いて、実施例２９と同様の操作により、淡黄色泡状の１－（２－（２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキソ－２，９－ジアザスピロ（５．５）ウンデカン－９－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン95mgを得た。
1H NMR (DMSO-d6)δ 1.48 (2 H, d, J=11.0 Hz), 1.82 (4 H, br. s.), 1.94 - 2.03 (2 H, m), 2.20 - 2.29 (2 H, m), 2.53 - 2.59 (2 H, m), 2.79 (2 H, d, J=10.1 Hz), 3.49 (2 H, br. s.), 3.99 (3 H, s), 4.23 (4 H, s), 4.34 - 4.40 (2 H, m), 6.61 - 6.72 (3 H, m), 6.81 (1 H, d, J=8.7 Hz), 7.46 (1 H, d, J=1.8 Hz), 7.87 (1 H, d, J=9.6 Hz), 8.28 (1 H, br. s.) (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde 39 mg and 2- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1-oxo- Using 60 mg of 2,9-diazaspiro (5.5) undecan-1-one hydrochloride in the same manner as in Example 29, 1- (2- (2- (2,3-3- Dihydrobenzo (1,4) dioxin-6-yl) -1-oxo-2,9-diazaspiro (5.5) undecan-9-yl) ethyl) -7-methoxy-1H- (1,5) naphthyridine 95 mg of 2-one was obtained.
1H NMR (DMSO-d6) δ 1.48 (2 H, d, J = 11.0 Hz), 1.82 (4 H, br.s.), 1.94-2.03 (2 H, m), 2.20-2.29 (2 H, m ), 2.53-2.59 (2 H, m), 2.79 (2 H, d, J = 10.1 Hz), 3.49 (2 H, br.s.), 3.99 (3 H, s), 4.23 (4 H, s ), 4.34-4.40 (2 H, m), 6.61-6.72 (3 H, m), 6.81 (1 H, d, J = 8.7 Hz), 7.46 (1 H, d, J = 1.8 Hz), 7.87 ( 1 H, d, J = 9.6 Hz), 8.28 (1 H, br.s.)
実施例３７
Figure JPOXMLDOC01-appb-I000121
Example 37
Figure JPOXMLDOC01-appb-I000121
（７－メトキシ－２－オキソ－２Ｈ－（１，５）－ナフチリジン－１－イル）酢酸31mg及び１’－（２，３－ジヒドロベンゾ（ｂ）（１，４）ジオキシン－６－イル）－８－アザスピロ（ビシクロ（３．２．１）オクタン－３，３’－ピロリジン）－５’－オン37mgを用いて、実施例５の第２工程と同様の操作により、白色固体状の１’－（２，３－ジヒドロベンゾ（ｂ）（１，４）ジオキシン－６－イル）－８－（２－（７－メトキシ－２－オキソ－（１，５）ナフチリジン－１（２Ｈ）－イル）アセチル）－８－アザスピロ（ビシクロ（３．２．１）オクタン－３，３’－ピロリジン）－５’－オン54mgを得た。
1H NMR (CHLOROFORM-d)δ 1.83 - 1.93 (2 H, m), 1.98 (1 H, d, J=3.7 Hz), 1.99 - 2.09 (4 H, m), 2.11 - 2.22 (1 H, m), 2.81 (2 H, d, J=5.0 Hz), 3.45 (2 H, d, J=1.8 Hz), 3.96 (3 H, s), 4.19 - 4.29 (4 H, m), 4.54 - 4.61 (1 H, m), 4.69 - 4.74 (1 H, m), 4.77 (1 H, d, J=16.0 Hz), 5.27 (1 H, d, J=16.0 Hz), 6.76 (1 H, d, J=9.6 Hz), 6.83 (1 H, d, J=8.7 Hz), 6.94 (1 H, dd, J=8.7, 2.3 Hz), 7.07 (1 H, d, J=2.3 Hz), 7.22 (1 H, d, J=2.3 Hz), 7.91 (1 H, d, J=9.6 Hz), 8.29 (1 H, d, J=2.3 Hz) (7-Methoxy-2-oxo-2H- (1,5) -naphthyridin-1-yl) acetic acid 31 mg and 1 ′-(2,3-dihydrobenzo (b) (1,4) dioxin-6-yl) Using a procedure similar to the second step of Example 5 using 37 mg of -8-azaspiro (bicyclo (3.2.1) octane-3,3′-pyrrolidin) -5′-one, '-(2,3-dihydrobenzo (b) (1,4) dioxin-6-yl) -8- (2- (7-methoxy-2-oxo- (1,5) naphthyridine-1 (2H)- Yl) acetyl) -8-azaspiro (bicyclo (3.2.1) octane-3,3′-pyrrolidin) -5′-one 54 mg was obtained.
1H NMR (CHLOROFORM-d) δ 1.83-1.93 (2 H, m), 1.98 (1 H, d, J = 3.7 Hz), 1.99-2.09 (4 H, m), 2.11-2.22 (1 H, m) , 2.81 (2 H, d, J = 5.0 Hz), 3.45 (2 H, d, J = 1.8 Hz), 3.96 (3 H, s), 4.19-4.29 (4 H, m), 4.54-4.61 (1 H, m), 4.69-4.74 (1 H, m), 4.77 (1 H, d, J = 16.0 Hz), 5.27 (1 H, d, J = 16.0 Hz), 6.76 (1 H, d, J = 9.6 Hz), 6.83 (1 H, d, J = 8.7 Hz), 6.94 (1 H, dd, J = 8.7, 2.3 Hz), 7.07 (1 H, d, J = 2.3 Hz), 7.22 (1 H, d, J = 2.3 Hz), 7.91 (1 H, d, J = 9.6 Hz), 8.29 (1 H, d, J = 2.3 Hz)
実施例３８
Figure JPOXMLDOC01-appb-I000122
Example 38
Figure JPOXMLDOC01-appb-I000122
（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒド36mg及び１’－（２，３－ジヒドロベンゾ（ｂ）（１，４）ジオキシン－６－イル）－８－アザスピロ（ビシクロ（３．２．１）オクタン－３，３’－ピロリジン）－５’－オン52mgを用いて、実施例２６と同様の操作により、泡状の１’－（２，３－ジヒドロベンゾ（ｂ）（１，４）ジオキシン－６－イル）－８－（２－（７－メトキシ－２－オキソ－（１，５）－ナフチリジン－１（２Ｈ）－イル）エチル）－８－アザスピロ（ビシクロ（３．２．１）オクタン－３，３’－ピロリジン）－５’－オン60mgを得た。
1H NMR (CHLOROFORM-d)δ 1.69 - 1.81 (4 H, m), 1.89 (2 H, dd, J=13.8, 3.2 Hz), 1.92 - 2.03 (2 H, m), 2.62 - 2.74 (4 H, m), 3.36 (2 H, br. s.), 3.45 (2 H, s), 3.98 (3 H, s), 4.20 - 4.27 (4 H, m), 4.34 (2 H, t, J=7.3 Hz), 6.75 (1 H, d, J=9.6 Hz), 6.83 (1 H, d, J=8.7 Hz), 6.97 (1 H, dd, J=8.7, 2.3 Hz), 7.08 (1 H, d, J=2.3 Hz), 7.25 (1 H, d, J=2.3 Hz), 7.85 (1 H, d, J=9.6 Hz), 8.28 (1 H, d, J=2.3 Hz) (7-Methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde 36 mg and 1 ′-(2,3-dihydrobenzo (b) (1,4) dioxin-6-yl)- By using the same procedure as in Example 26 using 52 mg of 8-azaspiro (bicyclo (3.2.1) octane-3,3′-pyrrolidin) -5′-one, foamy 1 ′-(2,3 -Dihydrobenzo (b) (1,4) dioxin-6-yl) -8- (2- (7-methoxy-2-oxo- (1,5) -naphthyridin-1 (2H) -yl) ethyl)- 60 mg of 8-azaspiro (bicyclo (3.2.1) octane-3,3′-pyrrolidin) -5′-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.69-1.81 (4 H, m), 1.89 (2 H, dd, J = 13.8, 3.2 Hz), 1.92-2.03 (2 H, m), 2.62-2.74 (4 H, m), 3.36 (2 H, br. s.), 3.45 (2 H, s), 3.98 (3 H, s), 4.20-4.27 (4 H, m), 4.34 (2 H, t, J = 7.3 Hz), 6.75 (1 H, d, J = 9.6 Hz), 6.83 (1 H, d, J = 8.7 Hz), 6.97 (1 H, dd, J = 8.7, 2.3 Hz), 7.08 (1 H, d , J = 2.3 Hz), 7.25 (1 H, d, J = 2.3 Hz), 7.85 (1 H, d, J = 9.6 Hz), 8.28 (1 H, d, J = 2.3 Hz)
実施例３９
Figure JPOXMLDOC01-appb-I000123
Example 39
Figure JPOXMLDOC01-appb-I000123
（７－フルオロ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒド26mgをクロロホルム2mLに懸濁し、トリエチルアミン0.01mLを加えて、室温にて３５分撹拌した。３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン31mgのクロロホルム溶液1mLを加えた。室温で１６時間撹拌後、トリアセトキシ水素化ホウ素ナトリウム48mgを加えて２．５時間撹拌した。飽和炭酸水素ナトリウム水溶液3mL及びクロロホルム5mLを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液5mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を分取用シリカゲル薄層クロマトグラフィーＮＨタイプ［富士シリシア株式会社製ＰＬＣプレートＮＨ、展開液；酢酸エチル）］で精製し、白色固体状の１－（２－（３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－イル）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン21mgを得た。
1H NMR (CHLOROFORM-d)δ 1.82 - 1.88 (2 H, m), 2.01 (2 H, dt, J=13.4, 3.6 Hz), 2.69 - 2.78 (6 H, m), 3.93 (2 H, s), 4.25 - 4.28 (2 H, m), 4.33 (4 H, dt, J=3.8, 2.0 Hz), 6.87 (1 H, d, J=9.6 Hz), 7.48 (1 H, dd, J=10.1, 1.8 Hz), 7.76 (1 H, s), 7.86 (1 H, s), 7.89 (1 H, d, J=9.6 Hz), 8.43 (1 H, d, J=1.8 Hz) 26 mg of (7-fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde was suspended in 2 mL of chloroform, 0.01 mL of triethylamine was added, and the mixture was stirred at room temperature for 35 minutes. 3- (2,3-dihydro- (1,4) dioxino (2,3-c) pyridin-7-yl) -1-oxa-3,8-diazaspiro (4.5) decan-2-one 31 mg 1 mL of chloroform solution was added. After stirring at room temperature for 16 hours, 48 mg of sodium triacetoxyborohydride was added and stirred for 2.5 hours. Saturated aqueous sodium hydrogen carbonate solution (3 mL) and chloroform (5 mL) were added, and the organic layer was separated. The organic layer was washed with 5 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography NH type [PLC plate NH, developed by Fuji Silysia Ltd., developing solution: ethyl acetate]] to give 1- (2- (3- (3- ( 2,3-dihydro- (1,4) dioxino (2,3-c) pyridin-7-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-yl) Ethyl) -7-fluoro-1H- (1,5) naphthyridin-2-one (21 mg) was obtained.
1H NMR (CHLOROFORM-d) δ 1.82-1.88 (2 H, m), 2.01 (2 H, dt, J = 13.4, 3.6 Hz), 2.69-2.78 (6 H, m), 3.93 (2 H, s) , 4.25-4.28 (2 H, m), 4.33 (4 H, dt, J = 3.8, 2.0 Hz), 6.87 (1 H, d, J = 9.6 Hz), 7.48 (1 H, dd, J = 10.1, 1.8 Hz), 7.76 (1 H, s), 7.86 (1 H, s), 7.89 (1 H, d, J = 9.6 Hz), 8.43 (1 H, d, J = 1.8 Hz)
実施例４０
Figure JPOXMLDOC01-appb-I000124
Example 40
Figure JPOXMLDOC01-appb-I000124
（７－フルオロ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）酢酸の塩酸塩36mg及び２－（２，３－ジヒドロ－ベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－３－オン33mgを用いて、実施例３と同様の操作により、無色粉末状の１－（２－（２－（２，３－ジヒドロベンゾ（ｂ）（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－８－イル）－２－オキソエチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン25.2mgを得た。
1H NMR (CHLOROFORM-d)δ 1.72 - 1.77 (2 H, m), 1.84 - 1.89 (2 H, m), 2.58 (2 H, s), 3.40 - 3.45 (1 H, m), 3.57 - 3.62 (1 H, m), 3.65 (2 H, s), 3.76 - 3.81 (1 H, m), 3.88 - 3.94 (1 H, m), 4.24 - 4.28 (4 H, m), 4.96 (1 H, d, J=16.0 Hz), 5.16 (1 H, d, J=16.5 Hz), 6.86 - 6.89 (2 H, m), 7.02 (1 H, dd, J=8.7, 2.8 Hz), 7.13 (1 H, d, J=2.8 Hz), 7.24 (1 H, dd, J=9.9, 2.1 Hz), 7.95 (1 H, d, J=9.6 Hz), 8.43 (1 H, d, J=2.1 Hz) (7-Fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) acetic acid hydrochloride 36 mg and 2- (2,3-dihydro-benzo (1,4) dioxin-6-yl)- Using the same procedure as in Example 3 using 33 mg of 3-oxo-2,8-diazaspiro (4.5) decan-3-one, 1- (2- (2- (2,3-3- Dihydrobenzo (b) (1,4) dioxin-6-yl) -3-oxo-2,8-diazaspiro (4.5) decan-8-yl) -2-oxoethyl) -7-fluoro-1H- ( 1,5) 25.2 mg of naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.72-1.77 (2 H, m), 1.84-1.89 (2 H, m), 2.58 (2 H, s), 3.40-3.45 (1 H, m), 3.57-3.62 ( 1 H, m), 3.65 (2 H, s), 3.76-3.81 (1 H, m), 3.88-3.94 (1 H, m), 4.24-4.28 (4 H, m), 4.96 (1 H, d , J = 16.0 Hz), 5.16 (1 H, d, J = 16.5 Hz), 6.86-6.89 (2 H, m), 7.02 (1 H, dd, J = 8.7, 2.8 Hz), 7.13 (1 H, d, J = 2.8 Hz), 7.24 (1 H, dd, J = 9.9, 2.1 Hz), 7.95 (1 H, d, J = 9.6 Hz), 8.43 (1 H, d, J = 2.1 Hz)
実施例４１
Figure JPOXMLDOC01-appb-I000125
Example 41
Figure JPOXMLDOC01-appb-I000125
（７－フルオロ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒドの塩酸塩37mg及び２－（２，３－ジヒドロ－ベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－３－オン44mgを用いて、実施例３９と同様の操作により、無色粉末状の１－（２－（２－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－３－オキソ－２，８－ジアザスピロ（４．５）デカン－８－イル）エチル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン31.4mgを得た。
1H NMR (CHLOROFORM-d)δ 1.71 (4 H, t, J=5.3 Hz), 2.46 (2 H, s), 2.50 - 2.55 (2 H, m), 2.59 - 2.62 (2 H, m), 3.56 (2 H, s), 4.22 - 4.26 (4 H, m), 4.32 (2 H, t, J=6.9 Hz), 6.82 - 6.87 (2 H, m), 7.02 (1 H, dd, J=8.7, 2.8 Hz), 7.12 (1 H, d, J=2.8 Hz), 7.49 (1 H, d, J=10.1 Hz), 7.88 (1 H, d, J=10.1 Hz), 8.42 (1 H, d, J=2.3 Hz) (7-Fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde hydrochloride 37 mg and 2- (2,3-dihydro-benzo (1,4) dioxin-6-yl)- The same operation as in Example 39 was carried out using 44 mg of 3-oxo-2,8-diazaspiro (4.5) decan-3-one and 1- (2- (2- (2,3-3- Dihydrobenzo (1,4) dioxin-6-yl) -3-oxo-2,8-diazaspiro (4.5) decan-8-yl) ethyl) -7-fluoro-1H- (1,5) naphthyridine 21.4 mg of 2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.71 (4 H, t, J = 5.3 Hz), 2.46 (2 H, s), 2.50-2.55 (2 H, m), 2.59-2.62 (2 H, m), 3.56 (2 H, s), 4.22-4.26 (4 H, m), 4.32 (2 H, t, J = 6.9 Hz), 6.82-6.87 (2 H, m), 7.02 (1 H, dd, J = 8.7 , 2.8 Hz), 7.12 (1 H, d, J = 2.8 Hz), 7.49 (1 H, d, J = 10.1 Hz), 7.88 (1 H, d, J = 10.1 Hz), 8.42 (1 H, d , J = 2.3 Hz)
実施例４２
Figure JPOXMLDOC01-appb-I000126
Example 42
Figure JPOXMLDOC01-appb-I000126
３－（７－フルオロ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）プロピオンアルデヒド150mg及び３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン186mgを用いて、実施例２６と同様の操作により、無色固体状の１－（３－（３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－２－オキソ－１－オキサ－３，８－ジアザスピロ（４．５）デカン－８－イル）プロピル）－７－フルオロ－１Ｈ－（１，５）ナフチリジン－２－オン42mgを得た。
1H NMR (CHLOROFORM-d)δ 1.60 (2 H, br. s.), 1.91 - 2.00 (4 H, m), 2.10 - 2.12 (2 H, m), 2.49 - 2.51 (2 H, m), 2.65 (4 H, br. s.), 3.75 (2 H, s), 4.27 - 4.34 (4 H, m), 6.90 (2 H, t, J=8.9 Hz), 7.04 (1 H, dd, J=8.9, 2.5 Hz), 7.12 (1 H, d, J=2.8 Hz), 7.83 (1 H, d, J=10.5 Hz), 7.93 (1 H, d, J=9.6 Hz), 8.46 (1 H, d, J=2.3 Hz) 3- (7-Fluoro-2-oxo-2H- (1,5) naphthyridin-1-yl) propionaldehyde 150 mg and 3- (2,3-dihydrobenzo (1,4) dioxin-6-yl) -1 1- (3- (3- (2,3-dihydro) of colorless solid was prepared in the same manner as in Example 26 using 186 mg of -oxa-3,8-diazaspiro (4.5) decan-2-one. Benzo (1,4) dioxin-6-yl) -2-oxo-1-oxa-3,8-diazaspiro (4.5) decan-8-yl) propyl) -7-fluoro-1H- (1,5 ) 42 mg of naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.60 (2 H, br.s.), 1.91-2.00 (4 H, m), 2.10-2.12 (2 H, m), 2.49-2.51 (2 H, m), 2.65 (4 H, br. S.), 3.75 (2 H, s), 4.27-4.34 (4 H, m), 6.90 (2 H, t, J = 8.9 Hz), 7.04 (1 H, dd, J = 8.9, 2.5 Hz), 7.12 (1 H, d, J = 2.8 Hz), 7.83 (1 H, d, J = 10.5 Hz), 7.93 (1 H, d, J = 9.6 Hz), 8.46 (1 H, d, J = 2.3 Hz)
実施例４３
Figure JPOXMLDOC01-appb-I000127
Example 43
Figure JPOXMLDOC01-appb-I000127
（２－（３－メトキシ－６－オキソ－６Ｈ－ピリド（２，３－ｂ）ピラジン－５－イル）酢酸の塩酸塩116mg及び３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン116mgを用いて、実施例３と同様の操作により、無色粉末状の３－（２，３－ジヒドロベンゾ（ｂ）（１，４）ジオキシン－６－イル）－８－（２－（３－メトキシ－６－オキソ－６Ｈ－ピリド（２，３－ｂ）ピラジン－５－イル）アセチル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン183mgを得た。
1H NMR (CHLOROFORM-d)δ 1.79 - 1.86 (2 H, m), 2.00 - 2.07 (2 H, m), 2.14 - 2.19 (1 H, m), 3.21 - 3.25 (1 H, m), 3.70 - 3.77 (3 H, m), 4.00 (3 H, s), 4.22 - 4.28 (4 H, m), 4.42 - 4.44 (1 H, m), 5.25 - 5.31 (2 H, m), 6.78 (1 H, d, J=9.6 Hz), 6.86 (1 H, d, J=8.7 Hz), 6.97 (1 H, dd, J=8.9, 2.5 Hz), 7.07 (1 H, d, J=2.8 Hz), 7.91 (1 H, d, J=9.6 Hz), 8.11 (1 H, s) 116 mg of hydrochloride of 2- (3-methoxy-6-oxo-6H-pyrido (2,3-b) pyrazin-5-yl) acetic acid and 3- (2,3-dihydrobenzo (1,4) dioxin- 6-yl) -1-oxa-3,8-diazaspiro (4.5) decan-2-one was used in the same manner as in Example 3 to obtain colorless powdery 3- (2,3-dihydro Benzo (b) (1,4) dioxin-6-yl) -8- (2- (3-methoxy-6-oxo-6H-pyrido (2,3-b) pyrazin-5-yl) acetyl) -1 There was obtained 183 mg of -oxa-3,8-diazaspiro (4.5) decan-2-one.
1H NMR (CHLOROFORM-d) δ 1.79-1.86 (2 H, m), 2.00-2.07 (2 H, m), 2.14-2.19 (1 H, m), 3.21-3.25 (1 H, m), 3.70- 3.77 (3 H, m), 4.00 (3 H, s), 4.22-4.28 (4 H, m), 4.42-4.44 (1 H, m), 5.25-5.31 (2 H, m), 6.78 (1 H , d, J = 9.6 Hz), 6.86 (1 H, d, J = 8.7 Hz), 6.97 (1 H, dd, J = 8.9, 2.5 Hz), 7.07 (1 H, d, J = 2.8 Hz), 7.91 (1 H, d, J = 9.6 Hz), 8.11 (1 H, s)
実施例４４
Figure JPOXMLDOC01-appb-I000128
Example 44
Figure JPOXMLDOC01-appb-I000128
２－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒド46mg及び３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｂ）ピリジン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン61mgを用いて、実施例２６と同様の操作により、無色泡状の３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｂ）ピリジン－６－イル）－８－（２－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）エチル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン60mgを得た。
1H NMR (CHLOROFORM-d)δ 1.83 - 1.88 (2 H, m), 1.98 - 2.04 (2 H, m), 2.69 - 2.78 (6 H, m), 3.94 (2 H, s), 3.98 (3 H, s), 4.22 - 4.25 (2 H, m), 4.36 - 4.38 (2 H, m), 4.42 - 4.43 (2 H, m), 6.74 (1 H, d, J=9.6 Hz), 7.16 (1 H, d, J=1.8 Hz), 7.23 - 7.26 (1 H, m), 7.76 (1 H, d, J=8.7 Hz), 7.84 (1 H, d, J=9.6 Hz), 8.28 (1 H, d, J=2.3 Hz) 46 mg of 2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde and 3- (2,3-dihydro- (1,4) dioxino (2,3-b) pyridine -6-yl) -1-oxa-3,8-diazaspiro (4.5) decan-2-one In the same manner as in Example 26, colorless foamy 3- (2,3- Dihydro- (1,4) dioxino (2,3-b) pyridin-6-yl) -8- (2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl ) -1-oxa-3,8-diazaspiro (4.5) decan-2-one 60 mg was obtained.
1H NMR (CHLOROFORM-d) δ 1.83-1.88 (2 H, m), 1.98-2.04 (2 H, m), 2.69-2.78 (6 H, m), 3.94 (2 H, s), 3.98 (3 H , s), 4.22-4.25 (2 H, m), 4.36-4.38 (2 H, m), 4.42-4.43 (2 H, m), 6.74 (1 H, d, J = 9.6 Hz), 7.16 (1 H, d, J = 1.8 Hz), 7.23-7.26 (1 H, m), 7.76 (1 H, d, J = 8.7 Hz), 7.84 (1 H, d, J = 9.6 Hz), 8.28 (1 H , d, J = 2.3 Hz)
実施例４５
Figure JPOXMLDOC01-appb-I000129
Example 45
Figure JPOXMLDOC01-appb-I000129
（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）酢酸の塩酸塩57mg及び３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｂ）ピリジン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン61mgを用いて、実施例３と同様の操作により、淡黄色粉末状の３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｂ）ピリジン－６－イル）－８－（２－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセチル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン59mgを得た。
1H NMR (DMSO-d6)δ 1.77 - 1.87 (2 H, m), 2.01 - 2.05 (2 H, m), 3.21 - 3.22 (1 H, m), 3.59 - 3.64 (1 H, m), 3.82 - 3.85 (3 H, m), 3.90 - 3.92 (1 H, m), 3.92 (3 H, s), 4.19 - 4.22 (2 H, m), 4.36 - 4.39 (2 H, m), 5.15 - 5.21 (1 H, m), 5.25 - 5.31 (1 H, m), 6.66 (1 H, d, J=9.6 Hz), 7.20 (1 H, d, J=1.8 Hz), 7.36 (1 H, d, J=8.7 Hz), 7.57 (1 H, d, J=8.7 Hz), 7.89 (1 H, d, J=9.6 Hz), 8.27 (1 H, d, J=1.8 Hz) (7-Methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetic acid hydrochloride 57 mg and 3- (2,3-dihydro- (1,4) dioxino (2,3-b) Pyridin-6-yl) -1-oxa-3,8-diazaspiro (4.5) decan-2-one was used in the same manner as in Example 3 to obtain 3- (2, 3-Dihydro- (1,4) dioxino (2,3-b) pyridin-6-yl) -8- (2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) ) Acetyl) -1-oxa-3,8-diazaspiro (4.5) decan-2-one (59 mg) was obtained.
1H NMR (DMSO-d6) δ 1.77-1.87 (2 H, m), 2.01-2.05 (2 H, m), 3.21-3.22 (1 H, m), 3.59-3.64 (1 H, m), 3.82- 3.85 (3 H, m), 3.90-3.92 (1 H, m), 3.92 (3 H, s), 4.19-4.22 (2 H, m), 4.36-4.39 (2 H, m), 5.15-5.21 ( 1 H, m), 5.25-5.31 (1 H, m), 6.66 (1 H, d, J = 9.6 Hz), 7.20 (1 H, d, J = 1.8 Hz), 7.36 (1 H, d, J = 8.7 Hz), 7.57 (1 H, d, J = 8.7 Hz), 7.89 (1 H, d, J = 9.6 Hz), 8.27 (1 H, d, J = 1.8 Hz)
実施例４６
Figure JPOXMLDOC01-appb-I000130
Example 46
Figure JPOXMLDOC01-appb-I000130
２－（６－オキソ－６Ｈ－ピリド（３，２－ｄ）ピリミジン－５－イル）酢酸の塩酸塩102mg及び３－（２，３－ジヒドロベンゾ（１，４）ジオキシン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン135mgを用いて、実施例３と同様の操作により、淡黄色粉末状の３－（２，３－ジヒドロベンゾ（ｂ）（１，４）ジオキシン－６－イル）－８－（２－（６－オキソ－６Ｈ－ピリド（３，２－ｄ）ピリミジン－５－イル）アセチル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン158mgを得た。
1H NMR (DMSO-d6)δ 1.75 - 1.83 (1 H, m), 1.84 - 1.90 (1 H, m), 2.02 - 2.06 (2 H, m), 3.59 - 3.65 (1 H, m), 3.78 - 3.82 (3 H, m), 3.83 - 3.88 (2 H, m), 4.19 - 4.22 (4 H, m), 5.21 - 5.34 (2 H, m), 6.85 (1 H, d, J=8.7 Hz), 6.98 (1 H, dd, J=8.7, 2.3 Hz), 7.09 - 7.15 (2 H, m), 7.98 (1 H, d, J=9.6 Hz), 9.03 (1 H, s), 9.05 (1 H, s) 2- (6-Oxo-6H-pyrido (3,2-d) pyrimidin-5-yl) acetic acid hydrochloride (102 mg) and 3- (2,3-dihydrobenzo (1,4) dioxin-6-yl)- 3- (2,3-dihydrobenzo (b) in the form of a pale yellow powder by the same operation as in Example 3 using 135 mg of 1-oxa-3,8-diazaspiro (4.5) decan-2-one (1,4) dioxin-6-yl) -8- (2- (6-oxo-6H-pyrido (3,2-d) pyrimidin-5-yl) acetyl) -1-oxa-3,8-diazaspiro (4.5) 158 mg of decan-2-one was obtained.
1H NMR (DMSO-d6) δ 1.75-1.83 (1 H, m), 1.84-1.90 (1 H, m), 2.02-2.06 (2 H, m), 3.59-3.65 (1 H, m), 3.78- 3.82 (3 H, m), 3.83-3.88 (2 H, m), 4.19-4.22 (4 H, m), 5.21-5.34 (2 H, m), 6.85 (1 H, d, J = 8.7 Hz) , 6.98 (1 H, dd, J = 8.7, 2.3 Hz), 7.09-7.15 (2 H, m), 7.98 (1 H, d, J = 9.6 Hz), 9.03 (1 H, s), 9.05 (1 H, s)
実施例４７
Figure JPOXMLDOC01-appb-I000131
Example 47
Figure JPOXMLDOC01-appb-I000131
（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）酢酸22mg及び３－（３－フルオロ－４－メチルフェニル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン26mgをクロロホルム10mLに懸濁し、トリエチルアミン65μL、１-エチル-３-（３-ジメチルアミノプロピル）カルボジイミド塩酸塩28mg及び１－ヒドロキシベンゾトリアゾール１水和物4mgを加え、室温にて１８時間撹拌した。反応混合物を酢酸エチル100mLで希釈し、水10mL、飽和食塩水10mLで順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア株式会社、Chromatorex-NH、溶離液：クロロホルム］で精製した。さらに精製物にクロロホルム10mL及びヘキサン150mLを加え、析出物を濾取、乾燥して白色固体状の３－（３－フルオロ－４－メチルフェニル）－８－（２－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセチル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン22mgを得た。
1H NMR (CHLOROFORM-d)δ 1.70 - 1.74 (1 H, m), 1.77 - 1.79 (1 H, m), 1.95 - 2.05 (2 H, m), 2.21 (3 H, s), 3.17 - 3.27 (4 H, m), 3.66 - 3.76 (2 H, m), 3.95 (3 H, s), 4.72 (1 H, d, J=16.1 Hz), 5.45 (1 H, d, J=16.1 Hz), 6.75 (1 H, d, J=9.9 Hz), 7.07 (1 H, d, J=1.7 Hz), 7.08 (1 H, d, J=2.1 Hz), 7.14 - 7.18 (1 H, m), 7.35 (1 H, dd, J=11.6, 2.1 Hz), 7.91 (1 H, d, J=9.9 Hz), 8.28 (1 H, d, J=2.5 Hz) 22 mg of (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetic acid and 3- (3-fluoro-4-methylphenyl) -1-oxa-3,8-diazaspiro (4. 5) Suspend decan-2-one (26 mg) in chloroform (10 mL), add triethylamine (65 μL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (28 mg) and 1-hydroxybenzotriazole monohydrate (4 mg) at room temperature. For 18 hours. The reaction mixture was diluted with 100 mL of ethyl acetate, washed successively with 10 mL of water and 10 mL of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Ltd., Chromatorex-NH, eluent: chloroform]. Further, 10 mL of chloroform and 150 mL of hexane were added to the purified product, and the precipitate was collected by filtration and dried to give 3- (3-fluoro-4-methylphenyl) -8- (2- (7-methoxy-2-) as a white solid. 22 mg of oxo-2H- (1,5) naphthyridin-1-yl) acetyl) -1-oxa-3,8-diazaspiro (4.5) decan-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.70-1.74 (1 H, m), 1.77-1.79 (1 H, m), 1.95-2.05 (2 H, m), 2.21 (3 H, s), 3.17-3.27 ( 4 H, m), 3.66-3.76 (2 H, m), 3.95 (3 H, s), 4.72 (1 H, d, J = 16.1 Hz), 5.45 (1 H, d, J = 16.1 Hz), 6.75 (1 H, d, J = 9.9 Hz), 7.07 (1 H, d, J = 1.7 Hz), 7.08 (1 H, d, J = 2.1 Hz), 7.14-7.18 (1 H, m), 7.35 (1 H, dd, J = 11.6, 2.1 Hz), 7.91 (1 H, d, J = 9.9 Hz), 8.28 (1 H, d, J = 2.5 Hz)
実施例４８
Figure JPOXMLDOC01-appb-I000132
Example 48
Figure JPOXMLDOC01-appb-I000132
２－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒド62mg及び３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン85mgを用いて、実施例２６と同様の操作により、無色固体状の３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）－８－（２－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）エチル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン95mgを得た。
1H NMR (CHLOROFORM-d)δ 1.82 - 1.88 (2 H, m), 1.98 - 2.03 (2 H, m), 2.69 - 2.78 (6 H, m), 3.93 (2 H, s), 3.97 (3 H, s), 4.24 - 4.27 (2 H, m), 4.31 - 4.34 (2 H, m), 4.37 (2 H, t, J=7.0 Hz), 6.74 (1 H, d, J=9.5 Hz), 7.15 (1 H, d, J=2.1 Hz), 7.75 (1 H, s), 7.82 - 7.87 (2 H, m), 8.28 (1 H, d, J=2.5 Hz) 2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde 62 mg and 3- (2,3-dihydro- (1,4) dioxino (2,3-c) pyridine -7-yl) -1-oxa-3,8-diazaspiro (4.5) decan-2-one In the same manner as in Example 26, the colorless solid 3- (2,3- Dihydro- (1,4) dioxino (2,3-c) pyridin-7-yl) -8- (2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl ) -1-oxa-3,8-diazaspiro (4.5) decan-2-one (95 mg) was obtained.
1H NMR (CHLOROFORM-d) δ 1.82-1.88 (2 H, m), 1.98-2.03 (2 H, m), 2.69-2.78 (6 H, m), 3.93 (2 H, s), 3.97 (3 H , s), 4.24-4.27 (2 H, m), 4.31-4.34 (2 H, m), 4.37 (2 H, t, J = 7.0 Hz), 6.74 (1 H, d, J = 9.5 Hz), 7.15 (1 H, d, J = 2.1 Hz), 7.75 (1 H, s), 7.82-7.87 (2 H, m), 8.28 (1 H, d, J = 2.5 Hz)
実施例４９
Figure JPOXMLDOC01-appb-I000133
Example 49
Figure JPOXMLDOC01-appb-I000133
（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）酢酸77mg及び３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン95mgを用いて、実施例４７と同様の操作により、無色固体状の３－（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）－８－（２－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセチル－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン111mgを得た。
1H NMR (CHLOROFORM-d)δ 1.70 - 1.79 (1 H, m), 1.86 - 1.93 (1 H, m), 1.97 - 1.99 (1 H, m), 2.05 - 2.10 (1 H, m), 3.21 - 3.28 (1 H, m), 3.64 - 3.70 (3 H, m), 3.90 - 3.97 (2 H, m), 3.92 (3 H, s), 4.21 - 4.24 (2 H, m), 4.29 - 4.31 (2 H, m), 4.78 (1 H, d, J=16.1 Hz), 5.34 (1 H, d, J=16.1 Hz), 6.73 (1 H, d, J=9.9 Hz), 7.04 (1 H, d, J=2.1 Hz), 7.70 (1 H, s), 7.83 (1 H, s), 7.87 (1 H, d, J=9.9 Hz), 8.25 (1 H, d, J=2.1 Hz) 77 mg of (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetic acid and 3- (2,3-dihydro- (1,4) dioxyno (2,3-c) pyridine-7 -Il) -1-oxa-3,8-diazaspiro (4.5) decan-2-one In the same manner as in Example 47, the colorless solid 3- (2,3-dihydro- (1,4) Dioxyno (2,3-c) pyridin-7-yl) -8- (2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetyl-1 There was obtained 111 mg of -oxa-3,8-diazaspiro (4.5) decan-2-one.
1H NMR (CHLOROFORM-d) δ 1.70-1.79 (1 H, m), 1.86-1.93 (1 H, m), 1.97-1.99 (1 H, m), 2.05-2.10 (1 H, m), 3.21- 3.28 (1 H, m), 3.64-3.70 (3 H, m), 3.90-3.97 (2 H, m), 3.92 (3 H, s), 4.21-4.24 (2 H, m), 4.29-4.31 ( 2 H, m), 4.78 (1 H, d, J = 16.1 Hz), 5.34 (1 H, d, J = 16.1 Hz), 6.73 (1 H, d, J = 9.9 Hz), 7.04 (1 H, d, J = 2.1 Hz), 7.70 (1 H, s), 7.83 (1 H, s), 7.87 (1 H, d, J = 9.9 Hz), 8.25 (1 H, d, J = 2.1 Hz)
実施例５０
Figure JPOXMLDOC01-appb-I000134
Example 50
Figure JPOXMLDOC01-appb-I000134
（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）酢酸18mg及び３－（２，３－ジヒドロベンゾ（ｂ）（１，４）ジチイン－６－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン26mgを用いて、実施例４７と同様の操作により、無色固体状の３－（２，３－ジヒドロベンゾ（ｂ）（１，４）ジチイン－６－イル）－８－（２－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセチル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン27mgを得た。
1H NMR (CHLOROFORM-d)δ 1.73 - 1.78 (1 H, m), 1.91 - 2.02 (2 H, m), 2.08 - 2.12 (1 H, m), 3.20 - 3.26 (4 H, m), 3.66 - 3.72 (4 H, m), 3.93 (3 H, s), 4.01 - 4.03 (1 H, m), 4.41 - 4.43 (1 H, m), 4.71 (1 H, d, J=16.1 Hz), 5.42 (1 H, d, J=16.1 Hz), 6.73 (1 H, d, J=9.5 Hz), 7.05 (1 H, d, J=2.1 Hz), 7.12 (1 H, d, J=8.7 Hz), 7.24 (1 H, d, J=2.5 Hz), 7.25 (1 H, d, J=2.1 Hz), 7.89 (1 H, d, J=9.5 Hz), 8.27 (1 H, d, J=2.1 Hz) 18 mg of (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetic acid and 3- (2,3-dihydrobenzo (b) (1,4) dithin-6-yl) -1 A colorless solid 3- (2,3-dihydrobenzo (b) (1) was prepared in the same manner as in Example 47 using 26 mg of -oxa-3,8-diazaspiro (4.5) decan-2-one. , 4) Dithiin-6-yl) -8- (2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetyl) -1-oxa-3,8-diazaspiro ( 4.5) 27 mg of decan-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.73-1.78 (1 H, m), 1.91-2.02 (2 H, m), 2.08-2.12 (1 H, m), 3.20-3.26 (4 H, m), 3.66- 3.72 (4 H, m), 3.93 (3 H, s), 4.01-4.03 (1 H, m), 4.41-4.43 (1 H, m), 4.71 (1 H, d, J = 16.1 Hz), 5.42 (1 H, d, J = 16.1 Hz), 6.73 (1 H, d, J = 9.5 Hz), 7.05 (1 H, d, J = 2.1 Hz), 7.12 (1 H, d, J = 8.7 Hz) , 7.24 (1 H, d, J = 2.5 Hz), 7.25 (1 H, d, J = 2.1 Hz), 7.89 (1 H, d, J = 9.5 Hz), 8.27 (1 H, d, J = 2.1 Hz)
実施例５１
Figure JPOXMLDOC01-appb-I000135
Example 51
Figure JPOXMLDOC01-appb-I000135
（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）酢酸32mg及び３－（チエノ（３，２－ｂ）チオフェン－２－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン43mgを用いて、実施例４７と同様の操作により、淡褐色固体状の８－（２－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセチル）－３－（チエノ（３，２－ｂ）チオフェン－２－イル）－１－オキサ－３，８－ジアザスピロ（４．５）デカン－２－オン45mgを得た。
1H NMR (CHLOROFORM-d)δ 1.79 - 1.86 (1 H, m), 2.00 - 2.08 (2 H, m), 2.12 - 2.19 (1 H, m), 3.18 - 3.22 (1 H, m), 3.67 - 3.71 (1 H, m), 3.76 - 3.82 (2 H, m), 3.95 (3 H, s), 4.07 - 4.09 (1 H, m), 4.46 - 4.49 (1 H, m), 4.72 (1 H, d, J=16.1 Hz), 5.45 (1 H, d, J=16.1 Hz), 6.70 (1 H, s), 6.75 (1 H, d, J=9.5 Hz), 7.08 (1 H, s), 7.18 (1 H, d, J=5.0 Hz), 7.25 - 7.26 (1 H, m), 7.91 (1 H, d, J=9.5 Hz), 8.29 (1 H, d, J=2.1 Hz) 32 mg of (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetic acid and 3- (thieno (3,2-b) thiophen-2-yl) -1-oxa-3,8 Using diazaspiro (4.5) decan-2-one 43 mg and following the same procedure as in Example 47, 8- (2- (7-methoxy-2-oxo-2H- (1, 5) 45 mg of naphthyridin-1-yl) acetyl) -3- (thieno (3,2-b) thiophen-2-yl) -1-oxa-3,8-diazaspiro (4.5) decan-2-one Obtained.
1H NMR (CHLOROFORM-d) δ 1.79-1.86 (1 H, m), 2.00-2.08 (2 H, m), 2.12-2.19 (1 H, m), 3.18-3.22 (1 H, m), 3.67- 3.71 (1 H, m), 3.76-3.82 (2 H, m), 3.95 (3 H, s), 4.07-4.09 (1 H, m), 4.46-4.49 (1 H, m), 4.72 (1 H , d, J = 16.1 Hz), 5.45 (1 H, d, J = 16.1 Hz), 6.70 (1 H, s), 6.75 (1 H, d, J = 9.5 Hz), 7.08 (1 H, s) , 7.18 (1 H, d, J = 5.0 Hz), 7.25-7.26 (1 H, m), 7.91 (1 H, d, J = 9.5 Hz), 8.29 (1 H, d, J = 2.1 Hz)
実施例５２
Figure JPOXMLDOC01-appb-I000136
Example 52
Figure JPOXMLDOC01-appb-I000136
（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）アセトアルデヒドの塩酸塩61mg及びＮ－（（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）メチル）－２－アザスピロ（３．３）ヘプタン－６－アミン80mgを用いて、実施例３９と同様の操作により、淡褐色固体状の１－（２－（６－（（（２，３－ジヒドロ－（１，４）ジオキシノ（２，３－ｃ）ピリジン－７－イル）メチル）アミノ）－２－アザスピロ（３．３）ヘプタン－２－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン33mgを得た。
1H NMR (CHLOROFORM-d)δ 1.82 -1.85 (2 H, m), 2.35 -2.38 (2 H, m), 2.71 (2 H, t, J=7.2 Hz), 3.16 -3.19 (1 H, m), 3.22 (2 H, s), 3.28 (2 H, s), 3.65 (2 H, s), 3.95 (3 H, s), 4.17 (2 H, t, J=7.2 Hz), 4.25 - 4.27 (2 H, m), 4.29 - 4.33 (2 H, m), 6.72 (1 H, d, J=9.9 Hz), 6.77 (1 H, s), 7.18 (1 H, d, J=1.7 Hz), 7.82 (1 H, d, J=9.9 Hz), 8.08 (1 H, s), 8.25 (1 H, d, J=2.5 Hz) 61 mg of (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) acetaldehyde hydrochloride and N-((2,3-dihydro- (1,4) dioxino (2,3-c ) Pyridin-7-yl) methyl) -2-azaspiro (3.3) heptane-6-amine was used in the same manner as in Example 39 to give 1- (2- (6- (((2,3-dihydro- (1,4) dioxyno (2,3-c) pyridin-7-yl) methyl) amino) -2-azaspiro (3.3) heptan-2-yl) ethyl)- 33 mg of 7-methoxy-1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.82 -1.85 (2 H, m), 2.35 -2.38 (2 H, m), 2.71 (2 H, t, J = 7.2 Hz), 3.16 -3.19 (1 H, m) , 3.22 (2 H, s), 3.28 (2 H, s), 3.65 (2 H, s), 3.95 (3 H, s), 4.17 (2 H, t, J = 7.2 Hz), 4.25-4.27 ( 2 H, m), 4.29-4.33 (2 H, m), 6.72 (1 H, d, J = 9.9 Hz), 6.77 (1 H, s), 7.18 (1 H, d, J = 1.7 Hz), 7.82 (1 H, d, J = 9.9 Hz), 8.08 (1 H, s), 8.25 (1 H, d, J = 2.5 Hz)
実施例５３
Figure JPOXMLDOC01-appb-I000137
Example 53
Figure JPOXMLDOC01-appb-I000137
１－（２－（２，７－ジアザスピロ（４．４）ノナ－２－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オンの塩酸塩19mg及び７－オキソ－（７，８）ジヒドロ－６Ｈ－ピリミド（５，４－ｂ）（１，４）オキサジン－２－カルバルデヒド10mgを用いて、実施例２３と同様の操作により、淡褐色固体状の２－（（７－（２－（７－メトキシ－２－オキソ－２Ｈ－（１，５）ナフチリジン－１－イル）エチル）－２，７－ジアザスピロ（４．４）ノナ－２－イル）メチル）－８Ｈ－ピリミド（５，４－ｂ）（１，４）オキサジン－７－オン10.5mgを得た。
1H NMR (CHLOROFORM-d)δ 1.78 - 1.95 (4 H, m), 2.52 -2.54 (2 H, m), 2.61 - 2.67 (2 H, m), 2.68 - 2.78 (6 H, m), 2.81 - 2.91 (2 H, m), 3.95 (3 H, s), 4.16 -4.21 (1 H, m), 4.53 - 4.59 (1 H, m), 4.70 (2 H, s), 6.87 (1 H, d, J=9.5 Hz), 7.15 (1 H, d, J=2.1 Hz), 7.84 (1 H, d, J=9.5 Hz), 8.20 (1 H, s), 8.27 (1 H, d, J=2.1 Hz) 1- (2- (2,7-diazaspiro (4.4) non-2-yl) ethyl) -7-methoxy-1H- (1,5) naphthyridin-2-one hydrochloride 19 mg and 7-oxo- (7,8) Dihydro-6H-pyrimido (5,4-b) (1,4) oxazine-2-carbaldehyde 10 mg was used in the same manner as in Example 23 to obtain a pale brown solid 2- ( (7- (2- (7-methoxy-2-oxo-2H- (1,5) naphthyridin-1-yl) ethyl) -2,7-diazaspiro (4.4) non-2-yl) methyl)- 10.5 mg of 8H-pyrimido (5,4-b) (1,4) oxazin-7-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.78-1.95 (4 H, m), 2.52 -2.54 (2 H, m), 2.61-2.67 (2 H, m), 2.68-2.78 (6 H, m), 2.81- 2.91 (2 H, m), 3.95 (3 H, s), 4.16 -4.21 (1 H, m), 4.53-4.59 (1 H, m), 4.70 (2 H, s), 6.87 (1 H, d , J = 9.5 Hz), 7.15 (1 H, d, J = 2.1 Hz), 7.84 (1 H, d, J = 9.5 Hz), 8.20 (1 H, s), 8.27 (1 H, d, J = 2.1 Hz)
実施例５４
Figure JPOXMLDOC01-appb-I000138
Example 54
Figure JPOXMLDOC01-appb-I000138
１－（２－（２，７－ジアザスピロ（４．４）ノナ－２－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オンの塩酸塩12.0mg及びシクロヘキサンカルバルデヒド12.4mgを用いて、実施例２３と同様の操作により、淡褐色固体状の１－（２－（７－シクロヘキシルメチル－２，７－ジアザスピロ（４．４）ノナ－２－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン10.3mgを得た。
1H NMR (CHLOROFORM-d) δ 0.82 - 0.91 (4 H, m), 1.09 - 1.27 (6 H, m), 1.63 - 1.73 (4 H, m), 1.74 - 1.92 (6 H, m), 2.49 - 2.60 (3 H, m), 2.67 - 2.80 (4 H, m), 3.98 (3 H, s), 4.36 (2 H, t, J=7.4 Hz), 6.74 (1 H, d, J=9.5 Hz), 7.23 (1 H, d, J=2.1 Hz), 7.84 (1 H, d, J=9.5 Hz), 8.28 (1 H, d, J=2.1 Hz) 12.0 mg of 1- (2- (2,7-diazaspiro (4.4) non-2-yl) ethyl) -7-methoxy-1H- (1,5) naphthyridin-2-one hydrochloride and cyclohexanecarbaldehyde 12.4 mg of 1- (2- (7-cyclohexylmethyl-2,7-diazaspiro (4.4) non-2-yl) ethyl)-was obtained in the same manner as in Example 23 using 12.4 mg. 10.3 mg of 7-methoxy-1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 0.82-0.91 (4 H, m), 1.09-1.27 (6 H, m), 1.63-1.73 (4 H, m), 1.74-1.92 (6 H, m), 2.49- 2.60 (3 H, m), 2.67-2.80 (4 H, m), 3.98 (3 H, s), 4.36 (2 H, t, J = 7.4 Hz), 6.74 (1 H, d, J = 9.5 Hz ), 7.23 (1 H, d, J = 2.1 Hz), 7.84 (1 H, d, J = 9.5 Hz), 8.28 (1 H, d, J = 2.1 Hz)
実施例５５
Figure JPOXMLDOC01-appb-I000139
Example 55
Figure JPOXMLDOC01-appb-I000139
１－（２－（２，７－ジアザスピロ（４．４）ノナ－２－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オンの塩酸塩11.4mg及び３－シクロヘキセン－１－カルバルデヒド9.6mgを用いて、実施例２３と同様の操作により、淡褐色固体状の１－（２－（７－（３－シクロヘキセン－１－イルメチル）－２，７－ジアザスピロ（４．４）ノナ－２－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オン9.9mgを得た。
1H NMR (CHLOROFORM-d) δ 1.17 - 1.33 (2 H, m), 1.61 - 1.92 (10 H, m), 1.94 - 2.18 (4 H, m), 2.25 - 2.45 (2 H, m), 2.49 - 2.64 (3 H, m), 2.67 - 2.80 (2 H, m), 3.97 (3 H, s), 4.36 (2 H, t, J=7.4 Hz), 5.62 - 5.71 (2 H, m), 6.75 (1 H, d, J=9.5 Hz), 7.23 (1 H, d, J=1.7 Hz), 7.84 (1 H, d, J=9.5 Hz), 8.28 (1 H, d, J=1.7 Hz) 1- (2- (2,7-diazaspiro (4.4) non-2-yl) ethyl) -7-methoxy-1H- (1,5) naphthyridin-2-one hydrochloride 11.4 mg and 3-cyclohexene 1- (2- (7- (3-Cyclohexen-1-ylmethyl) -2,7-diazaspiro (4) was prepared in the same manner as in Example 23 using 9.6 mg of 1-carbaldehyde. .4) Nona-2-yl) ethyl) -7-methoxy-1H- (1,5) naphthyridin-2-one 9.9 mg was obtained.
1H NMR (CHLOROFORM-d) δ 1.17-1.33 (2 H, m), 1.61-1.92 (10 H, m), 1.94-2.18 (4 H, m), 2.25-2.45 (2 H, m), 2.49- 2.64 (3 H, m), 2.67-2.80 (2 H, m), 3.97 (3 H, s), 4.36 (2 H, t, J = 7.4 Hz), 5.62-5.71 (2 H, m), 6.75 (1 H, d, J = 9.5 Hz), 7.23 (1 H, d, J = 1.7 Hz), 7.84 (1 H, d, J = 9.5 Hz), 8.28 (1 H, d, J = 1.7 Hz)
実施例５６
Figure JPOXMLDOC01-appb-I000140
Example 56
Figure JPOXMLDOC01-appb-I000140
１－（２－（２，７－ジアザスピロ（４．４）ノナ－２－イル）エチル）－７－メトキシ－１Ｈ－（１，５）ナフチリジン－２－オンの塩酸塩7.3mg及びテトラヒドロ－２Ｈ－チオピラン－４－カルバルデヒド10.1mgを用いて、実施例２３と同様の操作により、淡褐色固体状の７－メトキシ－１－（２－（７－（（テトラヒドロ－２Ｈ－チオピラン－４－イル）メチル）－２，７－ジアザスピロ（４．４）ノナ－２－イル）エチル）－１Ｈ－（１，５）ナフチリジン－２－オン5.8mgを得た。
1H NMR (CHLOROFORM-d) δ 1.18 - 1.55 (2 H, m), 1.60 - 1.91 (4 H, m), 2.02 - 2.17 (2 H, m), 2.25 (2 H, br. s.), 2.43 - 2.52 (2 H, m), 2.54 - 2.71 (5 H, m), 2.74 - 2.84 (6 H, m), 3.46 - 3.50 (2 H, m), 3.98 (3 H, s), 4.37 (2 H, br. s.), 6.74 (1 H, d, J=9.5 Hz), 7.24 (1 H, br. s.), 7.85 (1 H, d, J=9.5 Hz), 8.28 (1 H, d, J=2.1 Hz) 1- (2- (2,7-diazaspiro (4.4) non-2-yl) ethyl) -7-methoxy-1H- (1,5) naphthyridin-2-one hydrochloride 7.3 mg and tetrahydro-2H 7-Methoxy-1- (2- (7-((tetrahydro-2H-thiopyran-4-yl) in the form of a light brown solid was obtained in the same manner as in Example 23 using 10.1 mg of -thiopyran-4-carbaldehyde. 5.8) mg) -2,7-diazaspiro (4.4) non-2-yl) ethyl) -1H- (1,5) naphthyridin-2-one was obtained.
1H NMR (CHLOROFORM-d) δ 1.18-1.55 (2 H, m), 1.60-1.91 (4 H, m), 2.02-2.17 (2 H, m), 2.25 (2 H, br.s.), 2.43 -2.52 (2 H, m), 2.54-2.71 (5 H, m), 2.74-2.84 (6 H, m), 3.46-3.50 (2 H, m), 3.98 (3 H, s), 4.37 (2 H, br. S.), 6.74 (1 H, d, J = 9.5 Hz), 7.24 (1 H, br. S.), 7.85 (1 H, d, J = 9.5 Hz), 8.28 (1 H, d, J = 2.1 Hz)
　さらに、本発明の式［１］の化合物の有用性を以下の試験例で説明する。 Further, the usefulness of the compound of the formula [1] of the present invention will be described in the following test examples.
試験例１　感受性測定試験１
　被験物質をジメチルスルホキシドに溶解し、CLSI（Clinical and Laboratory Standards Institute）の標準法に準じた微量液体希釈法にて抗菌活性（MIC）を測定した。 Test example 1 Sensitivity measurement test 1
The test substance was dissolved in dimethyl sulfoxide, and antibacterial activity (MIC) was measured by a micro liquid dilution method according to the standard method of CLSI (Clinical and Laboratory Standards Institute).
　被験菌株は黄色ブドウ球菌（Staphylococcus aureus：MSSA，MRSA）を用いた。ハートインフュージョン寒天培地平板上、35℃で一夜培養した菌体を0.5McFarland相当になるようにミューラーヒントン培地に懸濁した。この懸濁液を10倍希釈し、接種菌液とした。接種菌液約0.005mLを被験物質を含むカチオン調整ミューラーヒントン培地（100μL/well）に接種し、35℃で一夜培養した。肉眼的に菌の発育が認められない最も低い被験物質濃度をMIC (μg/mL)とした。結果を表１に示す。数値が記載されていない箇所は試験をしていないことを示す。 The test strain used was Staphylococcus aureus (MSSA, MRSA). The cells cultured overnight at 35 ° C. on a heart infusion agar plate were suspended in Mueller Hinton medium so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. About 0.005 mL of the inoculated bacterial solution was inoculated into a cation-adjusted Mueller Hinton medium (100 μL / well) containing a test substance, and cultured overnight at 35 ° C. The lowest test substance concentration at which no bacterial growth was observed macroscopically was defined as MIC (μg / mL). The results are shown in Table 1. The part where the numerical value is not described indicates that the test is not performed.
Figure JPOXMLDOC01-appb-T000141
Figure JPOXMLDOC01-appb-T000141
Figure JPOXMLDOC01-appb-T000142
Figure JPOXMLDOC01-appb-T000142
試験例２　Staphylococcus aureus マウス全身感染試験
（１）接種菌液の調製
黄色ブドウ球菌（Staphylococcus aureus Smith 4）を約2×108 CFU／mLになるよう5％ムチン－生理食塩液に懸濁し、これを接種菌液とした。
（２）感染
接種菌液０．５mLを雄性ＩＣＲ系マウス（４週齢、日本ＳＬＣ）腹腔内へ接種（8～10×107 CFU／マウス）し、感染を惹起した。
（３）治療
実施例４で製造した化合物を１０％ヒドロキシプロピル化βシクロデキストリン水溶液で溶解し、菌接種１時間後に１ｍｇ／ｋｇ皮下投与した。一群８匹で実施した。
（４）効果の判定
感染治療効果は、菌接種７日後の生存数を指標とした。非治療群では菌接種１日後までに全例死亡したが、実施例４では菌接種７日後において８例中７例の生存が認められ、in vivoでの抗菌活性が示された。 Test Example 2 Staphylococcus aureus Mouse Systemic Infection Test (1) Preparation of Inoculum Bacteria Staphylococcus aureus Smith 4 is suspended in 5% mucin-saline solution to make about 2 × 10 8 CFU / mL. Was used as an inoculum.
(2) 0.5 mL of the inoculated bacterial solution was inoculated intraperitoneally into male ICR mice (4 weeks old, Japan SLC) (8-10 × 10 7 CFU / mouse) to induce infection.
(3) The compound produced in Treatment Example 4 was dissolved in a 10% hydroxypropylated β-cyclodextrin aqueous solution, and 1 mg / kg was subcutaneously administered 1 hour after the inoculation. A group of 8 animals was used.
(4) Judgment of effect The infection treatment effect was based on the survival number 7 days after bacterial inoculation. In the non-treatment group, all cases died by 1 day after the bacterial inoculation, but in Example 4, 7 out of 8 cases were observed 7 days after the bacterial inoculation, indicating in vivo antibacterial activity.
試験例３　黄色ブドウ球菌由来トポイソメラーゼIVに対する阻害活性の測定
　測定にはS. aureus Topoisomerase IV Decatenation Kit（Inspiralis社）を使用した。エッペンドルフチューブに5×Assay Buffer 198μL、0.1μg／μL kinetoplast DNA溶液66μL及び滅菌超純水462μLを添加し、反応基礎溶液Ａを調製した。PCRチューブに反応基礎溶液Ａ 22μL及び10倍濃度に調製した実施例２６の化合物又はシプロキサシン（CPFX）を3μL添加した。さらに、Dilution Bufferを用いて0.16U／μLに希釈したトポイソメラーゼIV溶液を5μL添加した。全量を37℃、30分間インキュベートした。
　反応後、反応停止液（0.1％ BPB含有0.5M EDTA）を5μL添加し、20μLを1％アガロースゲルにて電気泳動した。電気泳動後、アガロースゲルを2μg／mL 臭化エチジウム溶液中で染色し、画像を取り込み、各DNA量を求めた。
　すなわち、実施例２６の化合物又はCPFXを含まない酵素未添加群及び酵素添加群の単鎖で環状のDNAバンド量をそれぞれ0％及び100％として、反応産物が50％になる際の薬物濃度であるIC50（デカテネーション活性のIC50）を算出した。
　実施例２６の化合物及びCPFXのIC50は、いずれも1μg/mL以下であった。 Test Example 3 Measurement of inhibitory activity against Staphylococcus aureus-derived topoisomerase IV S. aureus Topoisomerase IV Decatenation Kit (Inspiralis) was used for measurement. To the Eppendorf tube, 198 μL of 5 × Assay Buffer, 66 μL of 0.1 μg / μL kinetoplast DNA solution and 462 μL of sterilized ultrapure water were added to prepare a reaction base solution A. To the PCR tube, 22 μL of reaction base solution A and 3 μL of the compound of Example 26 or cyproxacin (CPFX) prepared to a 10-fold concentration were added. Furthermore, 5 μL of topoisomerase IV solution diluted to 0.16 U / μL using Dilution Buffer was added. The whole volume was incubated at 37 ° C. for 30 minutes.
After the reaction, 5 μL of a reaction stop solution (0.5 M EDTA containing 0.1% BPB) was added, and 20 μL was electrophoresed on a 1% agarose gel. After electrophoresis, the agarose gel was stained in a 2 μg / mL ethidium bromide solution, an image was captured, and the amount of each DNA was determined.
That is, the amounts of single-stranded and circular DNA bands in the enzyme-free group and the enzyme-added group not containing the compound of Example 26 or CPFX were 0% and 100%, respectively, and the drug concentration when the reaction product was 50%. It was calculated some IC 50 (IC 50 deca Te Nation activity).
Both the compound of Example 26 and CPFX had an IC 50 of 1 μg / mL or less.
試験例４　黄色ブドウ球菌由来DNAジャイレースに対する阻害活性の測定
　測定にはS. aureus DNA Gyrase Supercoiling Assay Kit（Inspiralis社）を使用した。エッペンドルフチューブに5×Assay Buffer 210μL、1μg／μL relaxed pBR322 DNA溶液17.5μL及び滅菌超純水542.5μLを添加し、反応基礎溶液Ｂを調製した。PCRチューブに反応基礎溶液Ｂ 22μL及び10倍濃度に調製した実施例２６の化合物又はCPFXを3μL添加した。さらに、Dilution Bufferを用いて0.25U/μLに希釈したDNAジャイレース溶液を5μL添加した。全量を37℃、30分間インキュベートした。
　反応後、反応停止液を5μL添加し、20μLを1％アガロースゲルにて電気泳動した。泳動後、アガロースゲルを2μg／mL臭化エチジウム溶液中で染色し、画像を取り込み、各DNA量を求めた。
　すなわち、実施例２６の化合物又はCPFXを含まない酵素未添加群及び酵素添加群のスーパーコイル状のDNAバンド量をそれぞれ0％及び100％として、反応産物が50％になる際の薬物濃度であるIC50（スーパーコイリング活性のIC50）を算出した。
　実施例２６の化合物のIC50は、1μg/mL以下であった。一方、CPFXのIC50は、12μg/mLであった。 Test Example 4 Measurement of inhibitory activity against S. aureus-derived DNA gyrase S. aureus DNA Gyrase Supercoiling Assay Kit (Inspiralis) was used for measurement. A basic reaction solution B was prepared by adding 210 μL of 5 × Assay Buffer, 17.5 μL of relaxed pBR322 DNA solution and 542.5 μL of sterilized ultrapure water to an Eppendorf tube. To the PCR tube, 22 μL of reaction base solution B and 3 μL of the compound of Example 26 or CPFX prepared to a 10-fold concentration were added. Furthermore, 5 μL of DNA gyrase solution diluted to 0.25 U / μL using Dilution Buffer was added. The whole volume was incubated at 37 ° C. for 30 minutes.
After the reaction, 5 μL of a reaction stop solution was added, and 20 μL was electrophoresed on a 1% agarose gel. After electrophoresis, the agarose gel was stained in a 2 μg / mL ethidium bromide solution, an image was taken in, and the amount of each DNA was determined.
That is, the drug concentration when the reaction product is 50% when the amount of the supercoiled DNA band in the enzyme-free group and the enzyme-added group not containing the compound of Example 26 or CPFX is 0% and 100%, respectively. It was calculated IC 50 (IC 50 of supercoiling activity).
The IC 50 of the compound of Example 26 was 1 μg / mL or less. On the other hand, IC 50 of CPFX was 12 [mu] g / mL.
　試験例３及び４より、実施例２６の化合物は、両方の酵素に対しても強い阻害活性を示した。 From Test Examples 3 and 4, the compound of Example 26 showed strong inhibitory activity against both enzymes.
　本発明の複素環化合物又はその塩は、強い抗菌活性と高い安全性を有することから、優れた抗菌剤として有用である。 The heterocyclic compound of the present invention or a salt thereof is useful as an excellent antibacterial agent because it has strong antibacterial activity and high safety.

Claims (14)

  1. 式［Ｉ］
    Figure JPOXMLDOC01-appb-I000001
    （式中、
    Ｘ２とＹ１を結ぶ点線を含む結合は、単結合、又は二重結合を示し、
    Ｚ１は、窒素原子又は式ＣＲ１を示し、Ｚ２は、窒素原子又は式ＣＲ２を示し、Ｚ３は、窒素原子又は式ＣＲ３を示し、Ｚ４は、窒素原子又は式ＣＲ４を示し、Ｚ５は、窒素原子又は式ＣＲ５を示し、Ｚ６は、窒素原子又は式ＣＲ６を示し、
    Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、及びＲ６は、同一又は異なって、水素原子、Ｃ１－６アルコキシ基、ヒドロキシ基、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６ハロアルキル基、Ｃ１－６ハロアルコキシ基、Ｃ３－６シクロアルキル基、シアノ基、ニトロ基、Ｃ２－７アルカノイル基、単環複素環基、式－ＮＲ８Ｒ９、式－ＣＯ２Ｒ８、又は式－ＣＯＮＲ８Ｒ９を示し、
    Ｒ８、及びＲ９は、同一又は異なって、水素原子、又はＣ１－６アルキル基を示し、
    Ｘ１は、オキソ基で置換されていてもよいＣ１－４アルキレン基を示し、
    Ｘ２は、Ｘ２とＹ１を結ぶ点線を含む結合が単結合のとき結合手を示し、Ｘ２とＹ１を結ぶ点線を含む結合が二重結合のとき式ＣＨを示し、
    Ｙ１は、ヒドロキシ基、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６ヒドロキシアルキル基、Ｃ２－７アルカノイル基、フェニル基、式－ＮＲ１３Ｒ１４、式－ＣＯ２Ｒ１３、及び式－ＣＯＮＲ１３Ｒ１４からなる群から選ばれる１～３個の基で置換されていてもよい、以下の式群［ＩＩ］から選ばれるスピロ環基を示し、各スピロ環基中の窒素原子がＮ－オキシドであっても良く、
    Ｒ１３、及びＲ１４は、同一又は異なって、水素原子、又はＣ１－６アルキル基を示し、
    Figure JPOXMLDOC01-appb-I000002
    Ｘ３は、Ｃ１－４アルキレン基、式ＮＲ１０（ＣＨ２）ｍ、式ＳＯｎ、又は結合手を示し、
    Ｒ１０は、同一又は異なって、水素原子、又はＣ１－６アルキル基を示し、ｍ、及びｎは、同一又は異なって、０、１、又は２を示し、
    Ｒ７は、Ｃ３－６シクロアルキル基、Ｃ３－６シクロアルケニル基、アリール基、単環複素環基、又は二環複素環基を示し、
    ここで、該Ｃ３－６シクロアルキル基、Ｃ３－６シクロアルケニル基、アリール基、単環複素環基、及び二環複素環基は、Ｃ１－６アルコキシ基、ヒドロキシ基、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６ハロアルキル基、Ｃ１－６ハロアルコキシ基、Ｃ２－７アルカノイル基、単環複素環基、式－ＮＲ１１Ｒ１２ 、式－ＣＯ２Ｒ１１、及び式－ＣＯＮＲ１１Ｒ１２からなる群から選ばれる１～５個の置換基で置換されていてもよく、
    Ｒ１１、及びＲ１２は、同一又は異なって、水素原子、又はＣ１－６アルキル基を示す。）で表される化合物又はその塩。     Formula [I]
    Figure JPOXMLDOC01-appb-I000001
    (Where
    A bond including a dotted line connecting X 2 and Y 1 represents a single bond or a double bond,
    Z 1 represents a nitrogen atom or formula CR 1 , Z 2 represents a nitrogen atom or formula CR 2 , Z 3 represents a nitrogen atom or formula CR 3 , and Z 4 represents a nitrogen atom or formula CR 4 . Z 5 represents a nitrogen atom or formula CR 5 ; Z 6 represents a nitrogen atom or formula CR 6 ;
    R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are the same or different and each represents a hydrogen atom, a C 1-6 alkoxy group, a hydroxy group, a halogen atom, a C 1-6 alkyl group, C 1 -6 haloalkyl group, C 1-6 haloalkoxy group, C 3-6 cycloalkyl group, cyano group, nitro group, C 2-7 alkanoyl group, monocyclic heterocyclic group, formula -NR 8 R 9 , formula -CO 2 R 8 or the formula -CONR 8 R 9
    R 8 and R 9 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group,
    X 1 represents a C 1-4 alkylene group which may be substituted with an oxo group,
    X 2 represents a bond when a bond including a dotted line connecting X 2 and Y 1 is a single bond, and represents a formula CH when a bond including a dotted line connecting X 2 and Y 1 is a double bond,
    Y 1 represents a hydroxy group, a halogen atom, a C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 2-7 alkanoyl group, a phenyl group, a formula —NR 13 R 14 , a formula —CO 2 R 13 , and A spiro ring group selected from the following formula group [II], which may be substituted with 1 to 3 groups selected from the group consisting of the formula —CONR 13 R 14 , and a nitrogen atom in each spiro ring group May be N-oxide,
    R 13 and R 14 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group,
    Figure JPOXMLDOC01-appb-I000002
    X 3 represents a C 1-4 alkylene group, a formula NR 10 (CH 2 ) m , a formula SO n , or a bond,
    R 10 is the same or different and represents a hydrogen atom or a C 1-6 alkyl group; m and n are the same or different and represent 0, 1, or 2;
    R 7 represents a C 3-6 cycloalkyl group, a C 3-6 cycloalkenyl group, an aryl group, a monocyclic heterocyclic group, or a bicyclic heterocyclic group,
    Here, the C 3-6 cycloalkyl group, C 3-6 cycloalkenyl group, aryl group, monocyclic heterocyclic group, and bicyclic heterocyclic group are a C 1-6 alkoxy group, a hydroxy group, a halogen atom, A C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, a C 2-7 alkanoyl group, a monocyclic heterocyclic group, a formula —NR 11 R 12 , a formula —CO 2 R 11 , and May be substituted with 1 to 5 substituents selected from the group consisting of the formula -CONR 11 R 12 ,
    R 11 and R 12 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group. Or a salt thereof.
  2. Ｙ１が、ヒドロキシ基、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６ヒドロキシアルキル基、Ｃ２－７アルカノイル基、フェニル基、式－ＮＲ１３Ｒ１４、式－ＣＯ２Ｒ１３、及び式－ＣＯＮＲ１３Ｒ１４からなる群から選ばれる１～３個の基で置換されていてもよい、以下の式群［ＩＩＩ］から選ばれるスピロ環基であり、各スピロ環基中の窒素原子がＮ－オキシドであっても良く、
    Ｒ１３、及びＲ１４が、同一又は異なって、水素原子、又はＣ１－６アルキル基であり、
    Figure JPOXMLDOC01-appb-I000003
    Ｘ３が、Ｃ１－４アルキレン基、式ＮＲ１０、式ＳＯｎ、又は結合手であり、
    Ｒ１０が、同一又は異なって、水素原子、又はＣ１－６アルキル基であり、ｎが０、１、又は２であり、
    Ｒ７が、アリール基、単環複素環基、又は二環複素環基であり、
    ここで、該アリール基、単環複素環基、及び二環複素環基は、Ｃ１－６アルコキシ基、ヒドロキシ基、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６ハロアルキル基、Ｃ１－６ハロアルコキシ基、Ｃ２－７アルカノイル基、単環複素環基、式－ＮＲ１１Ｒ１２ 、式－ＣＯ２Ｒ１１、及び式－ＣＯＮＲ１１Ｒ１２からなる群から選ばれる１～５個の置換基で置換されていてもよく、
    Ｒ１１、及びＲ１２が、同一又は異なって、水素原子、又はＣ１－６アルキル基である請求項１に記載の化合物又はその塩。     Y 1 is a hydroxy group, a halogen atom, a C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 2-7 alkanoyl group, a phenyl group, a formula —NR 13 R 14 , a formula —CO 2 R 13 , and A spiro ring group selected from the following formula group [III], optionally substituted with 1 to 3 groups selected from the group consisting of the formula —CONR 13 R 14 , and a nitrogen atom in each spiro ring group May be N-oxide,
    R 13 and R 14 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group;
    Figure JPOXMLDOC01-appb-I000003
    X 3 is a C 1-4 alkylene group, a formula NR 10 , a formula SO n , or a bond,
    R 10 is the same or different and is a hydrogen atom or a C 1-6 alkyl group, n is 0, 1, or 2,
    R 7 is an aryl group, a monocyclic heterocyclic group, or a bicyclic heterocyclic group;
    Here, the aryl group, monocyclic heterocyclic group, and bicyclic heterocyclic group are a C 1-6 alkoxy group, a hydroxy group, a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1 1-6 selected from the group consisting of a -6 haloalkoxy group, a C 2-7 alkanoyl group, a monocyclic heterocyclic group, a formula —NR 11 R 12 , a formula —CO 2 R 11 , and a formula —CONR 11 R 12 May be substituted with a substituent of
    The compound or a salt thereof according to claim 1, wherein R 11 and R 12 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group.
  3. 　Ｚ１が式ＣＲ１であり、Ｚ４が式ＣＲ４であり、Ｚ６が式ＣＲ６である請求項１又は２に記載の化合物又はその塩。 The compound according to claim 1 or 2, or a salt thereof, wherein Z 1 is formula CR 1 , Z 4 is formula CR 4 , and Z 6 is formula CR 6 .
  4. 　Ｒ１、Ｒ４、及びＲ６が全て水素原子である請求項３に記載の化合物又はその塩。 The compound or a salt thereof according to claim 3, wherein R 1 , R 4 , and R 6 are all hydrogen atoms.
  5. 　Ｚ２が窒素原子又は式ＣＨである請求項１～４のいずれか１項に記載の化合物又はその塩。 The compound or a salt thereof according to any one of claims 1 to 4, wherein Z 2 is a nitrogen atom or the formula CH.
  6. 　Ｚ３が窒素原子又は式ＣＨである請求項１～５のいずれか１項に記載の化合物又はその塩。 The compound or a salt thereof according to any one of claims 1 to 5, wherein Z 3 is a nitrogen atom or the formula CH.
  7. 　Ｚ５が式ＣＲ５である請求項１～６のいずれか１項に記載の化合物又はその塩。 The compound or a salt thereof according to any one of claims 1 to 6, wherein Z 5 is formula CR 5 .
  8. 　Ｒ５が、Ｃ１－６アルコキシ基、又はハロゲン原子である請求項７に記載の化合物又はその塩。 The compound or a salt thereof according to claim 7, wherein R 5 is a C 1-6 alkoxy group or a halogen atom.
  9. 　Ｘ１がオキソ基で置換されていてもよいＣ１－２アルキレン基である請求項１～８のいずれか１項に記載の化合物又はその塩。 The compound or a salt thereof according to any one of claims 1 to 8, wherein X 1 is a C 1-2 alkylene group which may be substituted with an oxo group.
  10. 　Ｘ１がオキソ基で置換されたＣ１－２アルキレン基である請求項１～８のいずれか１項に記載の化合物又はその塩。 The compound or a salt thereof according to any one of claims 1 to 8, wherein X 1 is a C 1-2 alkylene group substituted with an oxo group.
  11. 　Ｙ１が、式群（ＩＩＩ）から選ばれる無置換のスピロ環基である請求項１～１０のいずれか１項に記載の化合物又はその塩。 The compound or a salt thereof according to any one of claims 1 to 10, wherein Y 1 is an unsubstituted spiro ring group selected from formula group (III).
  12. 　Ｙ１が、以下の式群［ＩＶ］から選ばれるスピロ環基である請求項１～１０のいずれか１項に記載の化合物又はその塩。
    Figure JPOXMLDOC01-appb-I000004
    The compound or a salt thereof according to any one of claims 1 to 10, wherein Y 1 is a spiro ring group selected from the following formula group [IV].
    Figure JPOXMLDOC01-appb-I000004
  13. 　Ｘ３が結合手である請求項１～１２のいずれか１項に記載の化合物又はその塩。 The compound or a salt thereof according to any one of claims 1 to 12, wherein X 3 is a bond.
  14. 　請求項１～１３に記載の化合物又はその塩を含有する抗菌剤。 An antibacterial agent comprising the compound according to claim 1 or a salt thereof.
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